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• Whole-genome methylation profiling of menstrual stem cells identifies novel biomarkers for endometriosis

  Endometriosis is a highly prevalent condition that remains underdiagnosed and poorly managed due to the lack of clinically validated biomarkers and limited understanding of its underlying pathophysiology. Although menstrual blood–derived stem cells (MenSCs) have been implicated in disease pathogenesis, their potential as a diagnostic source has not been systematically explored. We conducted a clinical study including 42 women (19 with endometriosis and 23 controls) to evaluate whether DNA methylation profiles from freshly isolated MenSCs could identify disease-specific biomarkers. Whole-genome DNA methylation sequencing identified differentially methylated regions (DMRs) enriched in genes associated with key features of endometriosis, including inflammation, tissue remodelling, and developmental processes. These DMRs robustly discriminated cases from controls, independently of technical and clinical confounders. Machine learning models trained and validated on these regions demonstrated strong diagnostic performance (specificity 83%, sensitivity 79%). Integration with an independent single-cell RNA sequencing dataset suggested that the identified DMRs may influence gene expression, supporting their biological relevance. Collectively, these findings highlight MenSC DNA methylation profiling as a promising, non-invasive strategy for early diagnosis and personalised management of endometriosis. (PubMed IDs will be provided once the manuscript is published.)

  Study EGAS50000001640

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis -Part II

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p<0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001003357

• Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis

  Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence, being highest in Saudi Arabia where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, followed by sequencing of these genes using a next-generation gene panel approach in further 785 samples. In addition to BRAF, N-RAS and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p<0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

  Study EGAS00001001788

• Target gene sequencing for human normal endometrial glands

  To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we conducted target sequencing of 112 genes for 1,298 endometrial glands and matched blood samples from 36 women. By collecting endometrial glands from different parts of the endometrium, we showed that multiple glands with the same somatic mutations occupied substantial areas of the endometrium. The 112 genes are as follows: ABCC1, ACRC, ANK3, ARHGAP35, ARID1A, ARID5B, ATCAY, ATM, ATR, BARD1, BCOR, BRCA1, BRCA2, BRD4, BRIP1, CAMTA1, CDC23, CDYL, CFAP54, CHD4, CHEK1, CHEK2, CTCF, CTNNB1, CUX1, DGKA, DISP2, DYNC2H1, EMSY, FAAP24, FAM135B, FAM175A, FAM65C, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FAT1, FAT3, FBN2, FBXW7, FGFR2, FRG1, GPR50, HEATR1, HIST1H4B, HNRNPCL1, HOOK3, KIAA1109, KIF26A, KMT2B, KMT2C, KRAS, LAMA2, LRP1B, MLH1, MON2, MRE11A, MSH2, MSH6, MTOR, NBN, PALB2, PHEX, PIK3CA, PIK3R1, PLXNB2, PLXND1, PMS2, POLE, POLR3B, PPP2R1A, PTEN, PTPN13, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RICTOR, SACS, SIGLEC9, SLC19A1, SLX4, SPEG, STT3A, TAF1, TAF2, TAS2R31, TFAP2C, TNC, TONSL, TP53, TTC6, UBA7, VNN1, WT1, XIRP2, ZBED6, ZC3H13, ZFHX3, ZFHX4, ZMYM4.

  Study EGAS00001005914

• FASTQ files of total RNA-Seq data of POPS control samples

  Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. These patients had no evidence of hypertension at booking and during pregnancy, did not experience pre-eclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome, gestational diabetes, or diabetes mellitus type I or type II and other obstetric complications. They delivered live babies with a birth weight percentile in the normal range (20-80th percentile), with no evidence of slowing in fetal growth trajectory. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003457

• Validation of a Haloplex platform for targeted re-sequencing of the exons of 25 genes

  We recently used the Agilent SureSelect platform to re-sequence a set of genes known to be mutated in human AML. The results from 10 AML DNA samples were very satisfactory, but the effort required was significant. Thus, we decided to re-sequence the same genes using the Haloplax system for target enrichment in 48 AML samples. We planned to do this using MiSeq and have data from a pilot of 3 samples. The data is promising but coverage appears pathcy so far. However, in order to get a better understanding of the data we will need deeper sequencing. We will need two lanes of HiSeq to get the same degree coverage as Sureselect. his data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001000603

• Somatic mutation burden and copy-number variation analysis in neurofibromatosis type 1-associated plexiform neurofibromas

  Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from biallelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time, e.g., there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0 - 8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.

  Study phs001403

• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

  Study phs001947

• Genomic Analysis of Mycosis Fungoides and Sézary Syndrome Identifies Recurrent Alterations in TNFR2

  Mycosis Fungoides (MF) and Sézary Syndrome (Sz) comprise the majority of Cutaneous T-Cell Lymphoma (CTCL) cases and are characterized by clinical heterogeneity. This array of symptoms includes skin patches, plaques and tumors as well as blood involvement and erythroderma. Because the genetic basis of CTCL is still poorly understood, we performed whole-exome sequencing on 11 MF/Sz samples and their matched, normal control DNA. Upon analyzing this data, we distilled a list of an additional 494 genes to be sequenced at depth. The majority of these 494 genes were sequenced in the exons alone, however, for a small subset of these genes we sequenced the entire genomic locus in search of structural variation events. This 494 gene targeted resequencing effort was performed upon 72 patients with MF/Sz and their matched, normal control DNA. An additional 5 MF/Sz and matched, normal DNA samples underwent whole genome amplification (WGA) prior to library preparation, which appears to have introduced mutations into these samples, however we also include them here. We additionally include 10 MF/Sz samples without a matched, normal control samples, 1 of which underwent WGA. In addition to primary disease samples, we also performed targeted resequencing on 4 CTCL cell lines (HH, MyLa, SeAx and Hut78) as well as on H9 cells (a subclone of Hut78 cells) and Jurkat cells, a T-ALL derived cell line that was used as an experimental system for our work. In sum, this data deposition includes exome and/or targeted resequencing from 92 individuals with 192 samples submitted.

  Study phs000913

• NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish

  The Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania (http://medschool.umaryland.edu/endocrinology/amish/research-program.asp). The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies. Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

  Study phs000956

• Modifier Genes in 21-hydroxylase Deficiency

  CAH is a genetic steroidogenesis disorder. The most common form, 21OHD, leads to cortisol deficiency and, in turn, an excess of androgen, a hormone that promotes the development and maintenance of male sex characteristics. As a result of this androgen excess, prepubescent males and newborn, prepubescent, and grown females exhibit mature masculine characteristics. The symptoms and severity of 21OHD vary among individuals with the disease and in adults versus children. The reasons for these differences are not yet known. Current therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary function. With more information about what genes or factors contribute to the severity of 21OHD, researchers may be able to better treat children and adults with the disease. This study will examine participants' DNA to determine what other genes may affect the severity of 21OHD and may make the disease milder in adults than in children This is a 3-day inpatient study. Once eligibility is confirmed through physical exam and blood analysis, eligible participants are admitted to the study site in the morning on the first study day. A blood sample is taken and participants receive one 10-mg pill of hydrocortisone. Heart rates and blood pressures are taken every 4 hours throughout the day. In the morning of Day 2, a blood sample will be obtained and a 24 hour urine collection will begin. On the morning of Day 3, another blood sample is obtained. Participants then receive intravenous cosyntropin, a synthetic form of a hormone that the body makes. About 1 hour after this, participants provide a final blood sample. Participants receive a pill of hydrocortisone prior to the end of the study.

  Study phs001313

• Mitochondrial DNA deletion detection in POLG patients

  Accumulation of deletions in the mitochondrial genome is a pathological hallmark of both aging and a broad range of neurometabolic disorders. Prior mtDNA deletion studies have been limited by reliance upon either long range PCR or NGS strategies that target specific regions of the mitochondrial genome. We developed an ultrasensitive high throughput sequencing process (LostArc) to identify and quantify all deletions in circular DNA molecules while minimizing interference from linear DNA and PCR artefacts. We applied this process to skeletal muscle biopsies from 19 unaffected individuals (aged 17 to 93 years) and from 22 patients with heritable mitochondrial disease (17 to 80 years) bearing pathogenic variants in POLG, the nuclear gene encoding the catalytic subunit of the mitochondrial replicative DNA polymerase ɣ (Pol ɣ). To our astonishment, LostArc revealed 35 million mtDNA deletions with ~470,000 unique deletion spans. This unprecedented volume of data enabled detailed and highly informative bioinformatics analyses. We show that ablation of mtDNA is sufficient to explain skeletal muscle phenotypes associated with aging and POLG-derived disease, with a clear threshold separating symptomatic and asymptomatic individuals. Unsupervised hierarchical clustering and principle component analysis reveal distinct age- and disease-correlated deletion patterns that implicate DNA replication by Pol ɣ in the formation of mtDNA deletions. Deletion patterns also point to active mtDNA replication but little or no purifying selection against deleted mtDNA by mitophagy in postmitotic muscle fibers. Monte Carlo simulations of varied hypotheses for deletion formation, based in part on competing models of mtDNA replication, suggest the observed patterns are most consistent with deletions initiated by replication fork stalling during strand displacement mtDNA synthesis. Note that sequence data for HEK293 can be found under BioProject PRJNA642884.

  Study phs002052

• Addictions: Genotypes, Polymorphisms, and Function/Human Genetic Correlates of Addictive Diseases

  Drug addiction continues to be a major medical and social problem. It is estimated that one million or more persons in the United States are currently addicted to heroin or prescription opioids, with millions more worldwide. Cocaine addiction and alcohol dependence are frequent comorbid conditions in persons with heroin/opioid dependence in addition to being major primary addictions. Many studies over the past thirty years have shown that these drugs disrupt physiologic systems, and that these disruptions may contribute to drug addiction and alcohol dependence and to relapse to drug or alcohol abuse following withdrawal and abstinence. Clinical observations suggest that individuals differ in their response to heroin, cocaine, and alcohol; however, little is known about specific underlying hereditary genetic factors which might influence individual susceptibility to the addictive properties of these substances. Studies also suggest that both common and distinct heritable factors account for the genetic variance in the susceptibility to the separate addictive diseases. We hypothesize that there is a heritable as well as environmental basis for the acquisition and persistence of, and relapse to, specific addictive diseases. Using samples from individuals without and with opioid and other specific drug dependence diagnoses and psychiatric comorbidities, genetic analyses will be used to determine association and linkage. All study subjects will be extensively characterized with respect to the addictive diseases, medical history, family medical addictive disease history; psychiatric comorbidity, and psychological profile, as well as ethnic/cultural background. A better understanding of the consequences of genetic contributions with respect to protection from, or susceptibility to, heroin/opioid addiction and related codependencies and comorbid conditions, could have enormous importance in both prevention and treatment of this problem.

  Study phs001109

• Gene mutation and rescue in congenital diaphragmatic hernia

  Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: Parents who were 1st cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes. This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway. These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.

  Study phs000485

• Analysis of Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

  High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.

  Study phs000413

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• PAGE: Global Reference Panel

  Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru A population sample of Easter Island (Rapa Nui), Chile Individuals of indigenous origin from Oaxaca, Mexico Individuals of indigenous origin from Honduras Individuals of indigenous origin from Colombia Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (https://bustamantelab.stanford.edu/). These comprise large public datasets to provide an open reference dataset for the world: The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs001033

• Glial Cell Line-Derived Neurotrophic Factor (GDNF) Polymorphisms and Anxiety, Depression

  GDNF gene variants were studied as possible risk factors of depression or anxiety on a young sample. The association study involved eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p=0.00070 and p=0.00138 for rs3812047 and rs3096140, respectively). Haplotype analysis confirmed the role of these SNPs (p=0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. This is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample. Reprinted from Kotyuk et. al., 2013 (Kotyuk, E., Keszler, G., Nemeth, N., Ronai, Z., Sasvari-Szekely, M., and Szekely, A. (2013). Glial Cell Line-Derived Neurotrophic Factor (GDNF) as a Novel Candidate Gene of Anxiety. PLoS One,8, (12) PMID: 24324616), with permission from Publisher (All content of articles published in PLOS journals is open access. You can read about our open access license here: http://www.plos.org/about/open-access/. To summarize, this license allows you to download, reuse, reprint, modify, distribute, and/or copy articles or images in PLOS journals, so long as the original creators are credited (e.g., including the article's citation and/or the image credit); Laura Perry; Staff EO;PLOS ONE)

  Study phs000713

• Breast Cancer in Blacks: Impact of Genomics, Healthcare Use and Lifestyle on Outcomes (BRIGHT)

  Young Black females bear a disproportionate burden of breast cancer (BC) mortality compared to White females and are underrepresented in clinical studies. It remains critical to understand factors that contribute to the high mortality from BC among young Black females in order to improve outcomes. The higher BC mortality rate among young Black females with breast cancer is partially attributed to the disproportionately higher proportions who develop the aggressive triple-negative breast cancer (TNBC). In addition to biologic factors, timely access to care, and lifestyle factors contribute to this disparity. Consequently, we sought to evaluate the interplay between biologic and non-biologic contributors to BC outcomes (i.e., BC disease-free survival (DFS)), and to better characterize the highly aggressive TNBC among young Black females based on distinct molecular subtypes. Ultimately, it is critical to assess both biologic and non-biologic factors to fully understand and address existing health disparities in this population. Through prior and subsequent recruitment of a population-based study of young Black females diagnosed with invasive breast cancer spanning 2009-2016, we: 1) assessed the contribution of biologic and non-biologic factors on BC-DFS observed among young Black females with BC, and 2) investigated molecular features of the subgroup with TNBC. Through this study, consented participants were asked to provide a saliva sample from which DNA was extracted for germline analyses, including germline inherited cancer genetic testing and Infinium Expanded Multi-Ethnic Genotyping Array. Breast cancer tumor specimens were also collected, and tumor RNA was extracted from viable FFPE tumor samples. Tumor RNA analyses included gene expression profiling through NanoString PAM50.Data that will be available through dbGaP for this study include SNP array data and PAM50 data.

  Study phs003466

• NHLBI TOPMed: Coronary Artery Risk Development in Young Adults (CARDIA)

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women, aged 18-30 years, were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less, and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), 2010-2011 (Year 25) and 2015-2016 (Year 30). In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination have differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease, such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements, such as weight and skinfold fat, as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20.Comprehensive phenotypic data for study participants are available through dbGaP phs000285.

  Study phs001612

• Blood Transcriptome Profiling Following Seizures

  The retrospective diagnosis or confirmation of a seizure, after the event, is very challenging. Many times clinicians can only use a patient's self-reported history. To further complicate the diagnosis, it is known that 20-30% of patients reporting a seizure actually suffer from psychogenic non-epileptic seizure (PNES). The patient has the behavior of a seizure, but does not suffer from brain seizure activity. Considerable time and resources are used to monitor PNES, and many patients undergo unnecessary therapy with anti-epileptic drugs. These resources could be more effectively used if we could confirm a seizure after the event (retrospective diagnosis). Here we propose a novel approach to distinguish seizures from PNES after the seizure event has happened.We have developed an accurate blood biomarker technology to diagnose acute brain injury, and assess chronic progression following brain injury. Previous studies support the premise that seizures affect blood RNA expression; here we assess temporal RNA expression pattern changes following seizure. We present preliminary preclinical data showing the discrimination of electric-stimulation evoked animal seizures. Here, we validate this maturing technology to assist with the discrimination of epileptic seizures from psychogenic non-epileptic seizures. We will analyze blood samples from patients undergoing video EEG monitoring in an epilepsy monitoring unit (Emory University Hospital, Atlanta GA). We expect 20% of these patients will have PNES. Once a patient has an EEG verified seizure, we will collect blood at various time points and identify biomarker RNA molecules in the blood. Blood samples will be collected from patients with non-verified seizures as control. These RNA expression values will be used to develop a predictive test for the occurrence of seizures. A biomarker gene panel will be developed from this exploratory project for validation in a larger patient population.

  Study phs003460

• Chromatin Landscape of BET Inhibitor-Treated CD8+ T-cells from Chronic Lymphocytic Leukemia Patients

  The pan-BET (bromodomain and extra-terminal) inhibitor, OPN-51107 (OPN5) was found to alleviate features of T-cell exhaustion in models of chronic lymphocytic leukemia (CLL). To evaluate if OPN5 treatment could relieve fixed chromatin states associated with terminal T-cell dysfunction, ATAC-sequencing was performed on CLL patient T-cells. Peripheral blood mononuclear cells (PBMCs) from 4 treatment-naïve CLL patients were treated ex vivo with 0.5 μM OPN5 or equivalent vehicle (DMSO) in the presence of T-cell activating stimuli (10 μg/mL anti-CD3 and 5 μg/mL anti-CD28) for 16 hours. Live CD8+ T-cells were then isolated via fluorescence-activated cell sorting, and approximately 100,000 viable CD8+ T-cells were subjected to ATAC-sequencing. Libraries were prepared using the Active Motif ATAC-seq kit and underwent paired-end sequencing (2 x 50 bp, 100 cycles) on an Illumina NovaSeq 6000 SP sequencer. Analysis of this data revealed that OPN5 treatment induces a unique chromatin landscape in CLL patient T-cells that is less like that of terminally exhausted T-cells and more like that of effector and memory T-cells. In particular, OPN5 treatment reduced chromatin accessibility at promoter regions of terminal exhaustion-associated genes (e.g., CD101, CCR5, LAG3, BATF3) and increased chromatin accessibility at promoter regions of genes associated with progenitor T-cell function (e.g., TCF7, IL2, CXCR5, IFNG). Individual raw sequencing (fastq) files and processed bigwig files (aligned to the hg38 human reference genome), as well as bigwig files for grouped OPN5- and vehicle-treated samples (aggregate of all 4 patient samples per treatment group) are available via authorized access request through dbGaP.

  Study phs003613

• Aberrant Activation of Wound Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells

  Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression.Using single-cell transcriptomics (scRNA-seq), we characterized genome– and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models.Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.

  Study phs003569

• Asian Immune Diversity Atlas (AIDA) sQTL

  Current efforts within the Human Cell Atlas (HCA) are largely focused on defining reference human cell types using a relatively small number of samples of predominantly European origin. However, the next phase of the HCA is likely to address the topic of human diversity by comprehensively characterizing variation in cell states across age, sex, population groups, diseases and environments. To spur this next phase, and also expand the geographical scope of the HCA, we propose an HCA-Asia seed network to generate an Asian Immune Diversity Atlas (AIDA). AIDA will generate transcriptome variation datasets from 5 major Asian population groups (Chinese, Japanese, Korean, Indian, Malay), define an atlas of Asian cell types and states, and characterize their variation associated with ethnicity, age and sex. We will also formalize a study design based on common controls that can in principle reduce technical artifacts in a broad range of comparative single cell studies. This study design will be complemented with novel algorithms designed to normalize datasets of interest against the common controls, to increase the robustness of biological inferences. In addition to providing new tools and resources to the HCA, this seed network will serve as a template for future comparative studies in the single cell field.The AIDA dataset consists of scRNA-seq (10x 5′ v2 scRNA-seq) and genotype (Illumina Infinium Global Screening Array v.3) data. In the AIDA splicing quantitative trait loci (sQTL) project, we identified 11,577 independent cis-sQTLs, 607 trans-sQTLs, and 107 dynamic sQTLs. The post-imputation genotype for the Japanese and Korean cohort will be available through dbGaP. The Singaporean (ethnically Chinese, Indian and Malay) genotypes require a data access application to the HELIOS Data Access Committee (helios_science@ntu.edu.sg). European samples are used as control.

  Study phs003848

• Impact of Genetic Variation on Response to GO Therapy in COG-AML Trials AAML03P1 and AAML0531

  The 340 de novo Acute Myeloid Leukemia (AML) patients (ages 1 month to 21 years) were enrolled in COG-AAML03P1 (NCT00070174). Everyone received standard chemotherapy regimen of ara-C, daunorubicin and etoposide (ADE) with addition of one 3 mg/m2 dose of Gemtuzumab Ozogamicin (GO) in induction 1 as well as in intensification II phase. The 1022 de novo AML patients (ages 0–30 years) were enrolled in COG-AAML0531 (NCT01407757). They were randomly assigned to receive either the standard ADE regimen (ADE arm, n = 511) or with the addition of one 3 mg/m2 dose of GO, during induction I as well as intensification II phase (ADE+GO arm, n = 511). Detailed study design, treatment regimen, and clinical outcomes of these two trials have been previously published (Cooper TM, Franklin J, Gerbing RB, et al., PMID:21766293 and Gamis AS, Alonzo TA, Meshinchi S, et al., PMID:25092781). The current study used genomic DNA from 1,225 pediatric patients treated in these two trials with 470 patients treated with standard chemotherapy in COG-AAML0531 (ADE arm) and 755 patients treated with addition of GO to standard therapy in COG-AAML03P1 and COG-AAML0531 trials (ADE+GO arm). The 132 SNPs in 42 genes within DNA-damage repair (DDR) pathways or genes implicated in mediating calicheamicin were selected for genotyping. These SNPs were genotyped using the Sequenom platform at the Biomedical Genomics Center, University of Minnesota. All SNPs had a call rate of more than 0.98 and were in accordance with the Hardy–Weinberg equilibrium. These genotypes were used to test for association with clinical endpoints as defined in the COG-AAML03P1 and COG-AAML0531 trials.

  Study phs003490

• Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

  In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that FGF8, a target of the PAX3-FOXO1 (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors FGFR1 and FGFR4, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, MEK, or ERK, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.

  Study phs004009

• Immunohistochemical and molecular pathological search in gastrointestinal tumors

  Purpose: RSPO fusions are recently identified recurrent genetic alterations in colorectal cancer (CRC), which lead to WNT pathway activation and are potential therapeutic targets. We aimed to investigate the clinicopathological and molecular features of RSPO fusion-positive CRCs. Experimental Design: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription polymerase chain reaction. RSPO fusion-positive tumors were characterized for their clinicopathological features and subjected to whole exome sequencing (WES). Results: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of 5 with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 females and 12 males with the median age of 64 years. Thirteen tumors were located in the right colon, 8 were in the left colon, and 8 were in the rectum. Histologically, most of the tumors (24/29, 83%) were classified as adenocarcinomas, not otherwise specified. However, about half of the tumors (13/29, 45%) had a focal or extensive mucinous component, which is significantly more frequent compared with RSPO fusion-negative tumors (13%; p = 8.1 �� 10-7). Four tumors (14%) were mismatch repair-deficient, three of which were associated with MLH1 promoter methylation. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 cases (93%). In contrast, pathogenic mutations in major WNT pathway genes other than RSPO fusions were virtually absent. The presence of an RSPO fusion tended to show shorter overall and recurrence-free survivals in stage II and III patients although the differences were not significant. Conclusions: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features. The mutual exclusivity with other WNT pathway gene alterations supports RSPO fusions as valid therapeutic targets in CRC.

  Study JGAS000538

• Paediatric Hepatic International Tumour Trial (JPLT2: PHITT)

  Hepatoblastoma (HBL) is the most common primary liver tumor in children. Despite their diversity in histopathological phenotype and clinical outcome, the underlying molecular aberrations have not been fully understood. Here we describe a comprehensive landscape of genomic, epigenomic, and transcriptomic heterogeneity among the 163 cases of HBLs and transitional liver cell tumors (TLCTs) collected in the multicenter clinical trial JPLT-2. The total numbers of mutational events in HBLs are very few (0.52 SNVs/Mb on exonic regions) but show a positive correlation with the age of onset. While dysregulation of Wnt-pathway related genes was observed (somatic deletion or mutations of CTNNB1 and germline or somatic mutations of APC) in 83.6% of the HBL cases, TERT promoter mutations are mainly in the elderly HBLs (> 8 years old), meeting with the proposed criteria of TLCT. These TLCT cases are clustered in the hypermethylated epigenotype in promoter and enhancer regions. Copy number analyses also revealed recurrent 11p15.5 UPD/LOHs including the IGF2/H19 region (31.6%), focal deletions in 4q35 (15.8%) and focal amplifications in 2q24.3 (7.0%) predominantly in the child and infant HBLs. Motif enrichment analysis of the specific hypomethylated enhancers in these HBL subtypes suggests specific binding of ASCL2, the regulatory transcription factor for definitive endoderm and digestive systems. Transcriptome and histochemical analysis revealed that ASCL2 is upregulated not in HCC and TLCT but in child and infant HBL, suggesting their ?cell of origin? derived from the premature hepatoblast with high proliferative potential such as intestinal epithelial cells. Systematic molecular profiling of HBL will provide a fundamental understanding of hepatoblast carcinogenesis and clues for risk stratification.

  Study JGAS000236

• Analysis of CD20 loss in patients treated with Mosunetuzumab

  CD20 is an established therapeutic target in B-cell malignancies. The CD20xCD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHL). Since target antigen loss is a recognized mechanism of resistance, we evaluated the contribution of CD20 expression to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial (ClinicalTrials.gov: NCT02500407) investigating mosunetuzumab monotherapy. CD20 was studied using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing performed centrally in biopsies collected prior to treatment, or as paired samples at pre-dose and on-treatment, or at-progression. Prior to treatment, most patients exhibited a high proportion of tumor cells expressing CD20; however, the proportion of CD20+ tumor cells in 14/293 (6%) patients was <10%. Analyses of paired biopsies from patients during treatment revealed that CD20 levels were maintained in 29/30 (97%), vs patients with samples at-progression, in which 11/32 (34%) showed CD20 loss. Reduced transcription or acquisition of truncating mutations explained most but not all cases of CD20 loss. In vitro modeling confirmed the effect of CD20 variants identified in clinical samples on reduction of CD20 expression and confirmed missense mutations in the extracellular domain that could block mosunetuzumab binding. This study expands knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to CD20-targeting bispecific antibodies and elucidates the underlying mechanisms for reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also establish the utility of readily-available IHC staining for CD20 as a tool to inform clinical decisions.

  Study EGAS50000000151

• Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

  Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

  Study EGAS00001002511

• A Multifactorial Tumor and Immune Cell Profile Determines Response to Immune Checkpoint blockade in Melanoma

  The complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models that interpret the anti-tumor immune response and predict clinical outcome. We have integrated genome-wide sequence and structural alterations with pre and on-therapy transcriptomic and T cell repertoire features for a cohort of 64 immunotherapy-naïve melanomas treated with anti-PD1 monotherapy or combined anti-PD1 and anti-CTLA4 therapy. While tumor mutation burden (TMB) was associated with improved response to therapy, expressed mutation burden was superior to TMB in predicting outcome. An increased pre-existing T cell density differentiated responding from non-responding tumors independent of therapy. Importantly, T cell repertoire reshaping determined by T cell receptor (TCR) clonotypic regressions and expansions reflected response to therapy such that a more dynamic repertoire predicted improved clinical outcome. Through whole-transcriptome analyses, we discovered differential abundance of B cell subsets in responding tumors, which highlights the importance of the interplay between pre-existing T and B cell immunity in shaping therapeutic response. Tumor temporal trajectories during therapy revealed distinct patterns of molecular response related to expressed mutation elimination or retention that accurately interpreted clinical response. High-dimensional genomic, transcriptomic and immune repertoire data were integrated by both a machine learning and a censored regression approach, resulting in a harmonized multi-modal predictor of response to immune checkpoint blockade. B cell abundance, expressed mutation load and tumor aneuploidy were combined to identify patients at high risk for recurrence, such that high risk patients had a significantly shorter progression-free survival (HR=9.18, 95% CI: 3.14-26.85, p=3.4e-06) especially in the anti-PD1/anti-CTLA4 group (HR=20.34, 95% CI: 4.08-101.32, p=1.68e-06).

  Study EGAS00001004548

• METABRIC

  Solid tumors are complex tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Normal cell contamination can dilute cancer cell information and tissue architecture is generally not reflected in molecular assays. To address these challenges, we developed a computational approach based on standard Haematoxylin and Eosin-stained sections and demonstrated its power in a discovery cohort of 323 breast tumors and an independent validation cohort of 241 tumors. First, to deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy-number profiles between samples. Second, we demonstrated that a predictor for survival integrating image-based and molecular features significantly outperforms classifiers based on single data types. Third, we described and validated a novel, independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative methods refine and complement molecular assays of tumor samples and could benefit all large-scale cancer studies.First, to deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy-number profiles between samples. Second, we demonstrated that a predictor for survival integrating image-based and molecular features significantly outperforms classifiers based on single data types. Third, we described and validated a novel, independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative methods refine and complement molecular assays of tumor samples and could benefit all large-scale cancer studies.

  Study EGAS00000000098

• MiR expression profiles of paired primary colorectal cancerand metastases by next-generation sequencing

  MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs aredifferentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expressionprofiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples,including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue withpaired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC withnormal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Twohundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR)o0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC withpotential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentiallyexpressed between pCRC and the corresponding metastases (FDR o0.1), consisting of five known miRs (miR-320b, miR-320d,miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). Theseresults indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition,miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosisor response to treatment in patients with advanced CRC

  Study EGAS00001001127

• The Genetic Landscape of BCL2 Break Negative Follicular Lymphoma

  Background: 15% of high and 50% of low stage FL lack the t(14;18). Nevertheless, most of these cases express BCL2 by so far unknown mechanisms. Principals/Methodology: To find molecular mechanisms, triggering FL-pathogenesis in t(14;18)-negative FL, the exonic SNV-profiles of 33 FL with and 16 FL without t(14;18) were assessed by whole exome-sequencing and external SNV-data integration. The SNV-profile of the whole exome-sequenced FL was correlated with copy number, LOH and gene-expression data. Finally, the N-glycosylation status was assessed (LympTrack assay) in a separate validation cohort. Results: SNVs in FL with and without t(14;18) affected different genes, but accumulated in similar pathways, e.g. apoptosis, epigenetic processes and cell cycle/proliferation. Mutations in genes associated with immune-response were more prominently and those associated with NFkB and N-glycosylation selectively enriched in t(14;18)-negative FL. ~50% of mutated genes showed BCL2-asociation at high confidence in FL with and without t(14;18). Moreover, among the genes mutated in t(14;18)-negative FL 555 (~1/3) were affected by copy number alterations and/or copy-neutral LOH, 125 were differently expressed between FL with and without t(14;18) (p<0.01) and 62 were differentially expressed and affected by copy number alterations and/or copy-neutral LOH. N-glycosylation was strongly reduced in t(14;18)-negative FL as compared to results reported for historical FL cohorts. Conclusion: These results suggest a stronger crosstalk with the microenvironment that may compensate for the lack of N-glycosylation and a diverse portfolio of SNVs that may contribute to the upregulation of BCL2 and FL pathogenesis in t(14;18)-negative FL.

  Study EGAS00001002164

• The Immune Microenvironment, Genome–Wide Copy Number Aberrations and Survival in Mesothelioma

  IntroductionResults of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as program cell death protein 1 (PD-1) and its ligand PD-L1 have not been well characterised in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates and genome-wide copy number status and correlated them to clinicopathological features.Patients and methodsTissue microarrays were constructed and stained with PD-L1(clone E1L3N, CST), CD4, CD8 and FOXP3 antibodies. PD-L1 positivity was defined as ≥5% membranous staining regardless of intensity and PD-L1+hi as ≥50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration (PGA) was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations (CNA) to other variables.ResultsAmongst 329 patients evaluated, PD-L1+ was detected in 130/311 (41.7%), but PD-L1+hi was only seen in 30/311 (9.6%). PD-L1+ correlated with non–epithelioid histology and increased infiltration with CD4+, CD8+ and FOXP3+ lymphocytes. PD-L1+hi expression correlated with worse prognosis (HR = 2.37; 95%CI= 1.57-3.56; P < 0.001) on univariate analysis, but not in multivariate analysis. Higher PGA was associated with epithelioid histology and poorer survival (HR = 1.59; 95%CI= 1.01-2.5; P = 0.04), but not PD-L1 expression.ConclusionPD-L1 expression was associated with non-epithelioid MPM, poor clinical outcome and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression, but was associated with poorer survival.

  Study EGAS00001002323

• UK10K NEURO EDINBURGH

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of subjects with schizophrenia recruited from psychiatric in-patient and out-patient facilities in Scotland. All diagnoses are based on standard research procedures and family histories are available. Patients have IQ>70 and the cohort includes the following groups: 100 cases with detailed clinical, cognitive and structural and functional neuroimaging phenotypes; 138 familial cases who are the probands of families where DNA has been collected from other affected members; 162 unrelated individuals. In most cases patients and their families may be re contacted to take part in further studies.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000117

• Whole exome sequencing of cell-free DNA reveals temporo-spatial heterogeneity and identifies treatment-resistant clones in neuroblastoma

  Background: Neuroblastoma (NB) displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Patients and Methods: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 NB patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of Single Nucleotide Variants (SNVs) and Copy Number Alterations (CNAs), with 41% and 93% of all detected alterations common to the primary NB and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate timepoints during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2. Conclusion: Modelisation of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating towards tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies.cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target.

  Study EGAS00001002705

• Toxigenic Clostridium perfringens isolated from at-risk pediatric inflammatory bowel disease patients

  With the goal of studying mucosal-associated bacteria and products detrimental to inflammatory bowel disease (IBD) patients, we directly cultured bacterial communities from mucosal biopsies and examined for detrimental traits. Focusing on red blood cell lysis, a virulence trait, communities from 5 of 9 patients exhibited hemolytic activity. Clostridium perfringens was isolated from each hemolytic community, and whole-genome sequencing confirmed presence of hemolytic toxins – alpha toxin in all 5 strains, perfringolysin O (PFO) in 4 strains, alveolysin in 2 strains – and absence of enterotoxins. In vitro cytotoxicity experiments demonstrated strain supernatants were toxic to various cell types located beneath the intestinal epithelial barrier, including endothelial, neuroblasts, and neutrophils, while impact on epithelial cells was less pronounced. These findings suggest C. perfringens may be damaging particularly when intestinal barrier integrity is compromised, such as in IBD patients. Further characterization using purified toxins and genetic insertion mutants confirmed PFO toxin was sufficient for cell toxicity. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion (DRG) neuron cells in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom. Strikingly, C. perfringens was detected in biopsies of 8 of 9 pediatric patients while not in all corresponding stool samples, and in other datasets, C. perfringens was in stool samples of IBD adults (18.7-27.1%) much more frequently versus healthy (5.1%). Our findings showcase C. perfringens may have an important pathogenic impact on IBD patients. Similar to Clostridioides difficile, routine monitoring of C. perfringens and PFO toxins in patients may be beneficial.

  Study EGAS50000000334

• Bladder cancer subtyping study across 4 atezo clinical trials

  Checkpoint inhibitors targeting the PD-1/PD-L1 interaction have revolutionized cancer therapy across many indications. In urothelial carcinoma (UC), several PD-1/PD-L1 inhibitors have been approved for treatment in localized and metastatic disease. While these agents provide durable clinical benefit in a number of patients, the majority do not respond. A better understanding of the molecular mechanisms underlying response and resistance is needed to tailor existing treatments and develop new therapeutics in UC. We profiled tumors from 2803 patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab in metastatic UC and muscle-invasive bladder cancer by RNA-seq, a targeted DNA panel, immunohistochemistry, and digital pathology. A machine learning algorithm identified four UC transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care was observed in immune and basal tumors (45% of patients). Digital pathology showed enrichment of human interpretable features in specific molecular subtypes, and a self-supervised approach could classify molecular subtypes from H&E slides with high accuracy, suggesting that machine-based image interpretation could accelerate tumor molecular profiling. Somatic alterations showed limited capacity to identify responders. Finally, mechanisms of benefit with PD-L1 blockade appeared different in immune and basal tumors, with immune tumors benefiting from B/plasma cell enrichment, while basal tumors benefited from granulocyte enrichment. This study represents the largest integration of UC molecular and curated clinical data in randomized clinical trials to date, paving the way for prospective clinical studies tailoring treatment regimens to specific tumor molecular subtypes in UC and other indications.

  Study EGAS50000000497

• The phase II Neo-Pembro trial: neoadjuvant pembrolizumab in stage IV high-grade serous ovarian cancer

  While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Nevertheless, some patients achieve lasting responses, emphasizing the need to understand how the tumor microenvironment and molecular characteristics influence ICI response. We hypothesized higher efficacy of ICI when used in the neoadjuvant setting and preceded by induction chemotherapy. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated patients with stage IV HGSOC who were planned for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation, through multiplexed immunofluorescence and immune-related gene expression. Our data provide evidence of immune activation, characterized by an increase in CD3+, CD8+, CD8+/FOXP3+ ratio, and TNF-α and interferon-γ signaling, and was most evident in major pathologic responders, which were 9/33 patients (27%, 95%CI 14-46) at time of surgery. Pathologic response was strongly associated with overall survival. At a median follow-up of 52.8 months, 8/9 major responders were alive, including 6 patients without recurrence, and 4 of 24 minor responders were alive, including one patient without recurrence. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as potential biomarkers, warranting further exploration. In a post-hoc comparison, major responders treated with pembro had significantly better overall survival than major responders in a historic cohort treated without pembro. Our data indicate that immune activation was stronger in the subset of major pathologic responders and these patients may derive long-term survival benefits from the addition of neoadjuvant pembro.

  Study EGAS50000000781

• Single-cell Transcriptome Profiling of Treatment-naïve and Post-treatment Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

  Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Investigation of cancer cells and tumor microenvironment (TME) following chemotherapy is critical for unraveling the mechanisms of resistance. In this study, we analyzed scRNA-Seq data from 56 CRCs including treatment-naïve tumors (25 microsatellite stable (MSS) tumors and 7 tumors with microsatellite instability (MSI)); and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). We observed in treatment-naïve MSS CRC that right-sided tumors are more immunogenic with higher numbers of B cells and CD8+ T memory effector cells than left-sided tumors. MSI CRC were even more immunogenic then MSS CRC and were characterized by elevated Tregs in their TME. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. We also observed two fibroblast subtypes in CRC, one of which was enriched in progressors and was associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated exhausted CD8+ T memory cells and monocytes suggesting a pro-inflammatory TME. In tumor cells in progressor group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related marker CD24. In summary, scRNA-Seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features of CRC based on location, metastasis status, MSI status and treatment response status.

  Study EGAS50000000830

• Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing

  We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double–stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non–IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non–IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.

  Study EGAS00001000962

• A molecular cell atlas of the human lung from single cell RNA sequencing

  Although single cell RNA sequencing studies have begun providing compendia of cell expression profiles, it has proven more difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here we describe droplet- and plate-based single cell RNA sequencing applied to ~75,000 human lung and blood cells, combined with a multi-pronged cell annotation approach, which have allowed us to define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 of 45 previously known cell types or subtypes and 14 new ones. This comprehensive molecular atlas elucidates the biochemical functions of lung cell types and the cell-selective transcription factors and optimal markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signaling interactions including sources and targets of chemokines in immune cell trafficking and expression changes on lung homing; and identifies the cell types directly affected by lung disease genes and respiratory viruses. Comparison to mouse identified 17 molecular types that appear to have been gained or lost during lung evolution and others whose expression profiles have been substantially altered, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions, and interactions are achieved in development and tissue engineering and altered in disease and evolution.

  Study EGAS00001004344

• Accurate mutation detection in leukemia by re-sequencing a cancer gene set

  With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using the Roche/454 technology coupled with Nimblegen sequence capture. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations.

  Study EGAS00001000268

• UK10K NEURO UKSCZ

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. These samples have been collected from throughout the UK and Ireland. The samples fall into two main categories, approximately 500 have a full diagnostic work up. A proportion of these are cases with a positive family history of schizophrenia, either collected as sib-pairs or from multiplex kindred's. The second group consist mainly of >300 samples that have been systematically collected within South Wales and in addition to full diagnostic work up have undergone detailed cognitive testing. All samples have obtained a DSM IV diagnosis of schizophrenia or schizoaffective disorder.For further information on this cohort please contact Michael Owen (OwenMJ@cardiff.ac.uk).

  Study EGAS00001000123

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. We performed multi-omic analysis including whole-exome, RNA and miRNA sequencing and quantification of 126 proteins in a series 34 LCCL coupled with a screening of 29 anti-cancer agents. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular "proliferation class" of HCC. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity that was more potent than FGFR4 inhibitors in tumor cells depending on the FGF19/FGFR4 pathway. Moreover, we showed that FGF19 amplification was only functional in tumor cells that retained a hepatocyte differentiation program with expression of FGFR4, KLB and NR1H4 highlighting the complex interplay between the genomic and transcriptomic context in drug response. We also identified drugs/combination that could target efficiently the transcriptomic "progenitor subclass of HCC", as well as specific genetic contexts such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib, respectively. LCCL represent relevant preclinical models for drug-biomarker discovery in HCC and enabled to identify molecular contexts linked with particular therapeutic vulnerabilities that may be useful to stratify patients in future clinical trials

  Study EGAS00001003536

• Combining a Universal Telomerase Based Cancer Vaccine with Ipilimumab in Patients with Metastatic Melanoma - Five-year Follow up of a Phase I/IIa Trial

  Background Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma. Patients and methods In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production. Results Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years. Conclusion Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.

  Study EGAS00001005253

• Exploration of coding and non-coding variants in cancer using GenomePaint.

  GenomePaint (https://proteinpaint.stjude.org/genomepaint) is a dynamic visualization platform for whole-genome, whole-exome, transcriptome, and epigenomic data, featuring a novel design that captures the inter-relatedness between DNA variations and RNA expression. Regulatory non-coding variants can be inspected and discovered along with coding variants, and their functional impact further explored by examining 3D genome and/or ChIP-seq data generated from cancer cell lines. Further, GenomePaint correlates mutation and expression patterns with patient outcomes, and can display external data such as adult cancer datasets and user-provided custom tracks. We used GenomePaint to analyze multi-omics data from 3,652 pediatric cancers representing 16 histotypes, and demonstrate the visualization features through examples, including two that led to new insights into oncogenic mechanisms in pediatric cancer. The first is the discovery of a new class of pathogenic recurrent variants that cause aberrant splicing, disrupting the RING domain of CREBBP, a driver gene frequently mutated in relapsed pediatric leukemia. The second is the cis-activation of the MYC oncogene in a subset of B-lineage acute lymphoblastic leukemia (B-ALL) via duplication of the NOTCH1-MYC enhancer (N-ME), previously discovered only in T-lineage ALL. The regulatory impact of N-ME enhancer amplification was initially confirmed by allelic imbalance in published gene expression and ChIP-seq data and verified by additional Capture-C and fluorescence in situ hybridization data generated by follow-up experiments. These examples demonstrate the power of GenomePaint in enabling not only data visualization but also integrative genomic analysis that can lead to novel biological insight for follow-up experimental validation.

  Study EGAS00001004669

• Combination of CDK4/6 with BET-bromodomain and PI3K/mTOR inhibitors in medulloblastoma in vitro and in vivo

  Despite improvement in the treatment of medulloblastoma (MB) over the last years, numerous patients with MYC- and MYCN-driven tumors still fail the current therapeutic regimen. The retinoblastoma (RB) pathway is often compromised in MB with RB remaining intact suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. Using tumor lines grown in stem cell conditions referred as tumorspheres as well as tumor cells freshly dissociated from the brain of mice harboring intracranial patient-derived xenografts (PDX) of Group3 (G3) and Sonic Hedgehog (SHH) MB, we conducted high throughput drug combination screens using the CDK4/6 inhibitor (CDK4/6i) ribociclib as an anchor and 87 oncology drugs approved by FDA or currently in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib’s inhibition of proliferation in G3 and SHH MB. A reverse combination screen using BET inhibitor JQ1 as the anchor, revealed the three FDA approved CDK4/6i as the most potentiating drugs. Those synergistic combinations were tested in vivo in mice intracranially implanted with G3 and SHH MB tumor cells. Ribociclib showed single agent activity in several in vivo MB models. However, despite in vitro synergy, combinations of ribociclib with JQ1 and ribociclib with the PI3K/mTOR inhibitor paxalisib failed to improve the survival of MB bearing mice compared to ribociclib alone. Our data illustrates the difficulty in translating in vitro findings to in vivo for brain tumors partly due to insufficient free brain concentration and altered signaling pathways activation in vitro compared to in vivo.

  Study EGAS00001006286

• Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM

  Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.

  Study EGAS00001007286

• Transcriptomics-driven classification of ALAL

  Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis subtype of acute leukemia that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to comprehensively detect genetic lesions in RNA-sequencing data (n=23) with a sensitivity >90%, as confirmed by targeted DNA sequencing. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (n=145), B-ALL (n=223) and T-ALL (n=85) cases. In a principal component analysis, ALALs did not form a separate group, but clustered with AML, B-ALL or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 20/23 ALALs into myeloid-, B- or T-lymphoid leukemia. These 20 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, ALAL GEPs were deconvoluted with single-cell transcriptional profiles of normal hematopoietic cells using CIBERSORTx, revealing enrichment for signatures of lineages corresponding to the leukemic type predicted by our algorithm. The classifier was validated on an external ALAL cohort (n=24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA-sequencing data can accurately classify most ALAL cases. The pipeline and classifier developed in our study are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.

  Study EGAS00001007967

• The University of Tasmania MS Stem Data Access Committee

  Data access committee for data related to the Multiple Sclerosis Stem (MS Stem) biobank. A biobank of human induced pluripotent stem cell (iPSC) lines. MS Stem is a biobank of human induced pluripotent stem cell (iPSC) lines, derived from people living with and without multiple sclerosis. The biobank provides researchers with fully characterised iPSC lines from well phenotyped and genotyped individuals. This provides a unique opportunity to research the pathophysiology of MS in human cell models or conduct preclinical screening of putative therapeutics.

  Dac EGAC50000000120

• Exome Sequencing for Head and Neck Cancer Susceptibility

  This study seeks to find low frequency or rare genetic variants in genes carried by subjects from families with unexplained familial risk of head and neck cancer. Whole exome sequencing was used to identify genetic variation in head and neck cancer cases.

  Study phs002571

• Comprehensive survey for the construction of an integrated database of food, gut microbiome, and health information (the "Sukoyaka Health Survey")

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 59 healthy Japanese. We analyzed some participants living in Nagasaki. Shotgun metagenomic sequencing of fecal microbiome were analyzed.

  Study JGAS000681

• Targeted sequencing data of regulatory regions in 200 Spanish ASD trios

  This dataset consists of genomic sequencing data obtained through targeted sequencing of regulatory regions ( 85,394 human cCREs from ENCODE v2, version 2, https://screenv2.wenglab.org/) in 200 ASD (Autism Spectrum Disorder) trios (father and mother unaffected and proband affected)(600 samples total). Sequencing was carried out at the Centre for Genomic Regulation (CRG), Barcelona, Spain. Uploaded files are .vcf (600 samples). The goals of our study were to detect de novo and inherited variants in ASD probands. Sequencing data were obtained in an Illumina NovaSeq6000 instrument.

  Dac EGAC50000000695

• DAC for "Transcriptome analysis of human iPSC-derived microglia in a novel human 3D cortical tissue model"

  scRNA-seq analysis of human iPSC-derived microglia in a novel, human in vitro 3D cortical tissue model. Samples include three distinct conditions (each as biological duplicates): wild-type microglia extracted from cultures after 1 month (WT_1mo) and 3 months (WT_3mo) of culturing, as well as knock-in microglia extracted from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo).

  Dac EGAC50000000303

• Jeju Genome Project DAC

  This Data Access Committee (DAC) evaluates and manages access requests for large-scale genomic and phenotypic datasets generated as part of the Jeju Genome Project (JGP). The committee's mission is to facilitate responsible data sharing to advance precision medicine and population genetics. The DAC ensures that data access is granted only to bona fide researchers who agree to the terms of the Data Access Agreement (DAA) and whose proposed research is strictly consistent with the informed consent provided by the participants and the ethical guidelines of the project.

  Dac EGAC50000000938

• A first-in-human clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy

  iPSC-derived corneal endothelial cell substitutes recover pathological corneal edema. No adverse reactions are observed after one year follow-up. Gene mutations may appear despite whole genome sequencing of the master cell bank. This study contains WGS data.

  Study EGAS50000000672

• Nucleosome footprinting in plasma cell-free DNA for diagnosis of ovarian cancer

  Fragmentation patterns of plasma cell-free DNA (cfDNA) are known to reflect nucleosome positions of cell types contributing to cfDNA. Based on cfDNA fragmentation patterns, the deviation in nucleosome footprints was quantified between diagnosed ovarian cancer patients and healthy individuals.

  Study EGAS00001005361

• ERDERA WES reanalysis - DPF2 Batch 7

  This dataset comprises processed genomic data from 1000 samples, corresponding to 1000 whole-exome sequencing experiments from ERDERA Data Processing Freeze 2. Data files include CRAM, gVCF (containing short variants, copy number variants, and structural variants), RoH (BED), B-allele frequencies (BW), and variant IGV visualizations (XML). Associated phenotypic and pedigree information for all samples is also included.

  Dataset EGAD50000002503

• RNA-seq and ATAC-seq data for ex vivo expanded T cells

  This dataset contains bulk RNA-seq and ATAC-seq data generated from naïve CD8+ T cells isolated from PBMCs of three healthy donors and stimulated ex vivo under multiple conditions. The dataset comprises 30 samples in total, including 15 RNA-seq samples and 15 ATAC-seq samples. Paired-end sequencing was performed on the Illumina NovaSeq 6000 platform. Raw data are provided as gzipped paired FASTQ files.

  Dataset EGAD50000002471

• TenK10K Phase 1: scRNA-seq fastq format sequencing data

  Single cell RNA-sequencing data for PBMCs from the Tenk10k Phase 1 cohort (1925 individuals post-QC). Libraries were prepared using the 10x Genomics 3’ Chromium Next GEM Single Cell HT V3.1 kit and sequenced on the NovaSeq 6000 platform. This analysis consists of 4,768 fastq format files in 1,192 runs, and an analysis which provides the relationship of 298 library pool samples to 1,925 individual samples.

  Dataset EGAD50000002517

• Aligned FOS RNA sequencing data

  Total RNA-sequencing Paired-End was performed by GenomeScan (Leiden, the Netherlands) on the NovaSeq6000 platform for full-length FOS (FOS FL), truncated FOS (FOSΔ), a FOS isoform with an L376N mutation (FOS mut), untransduced fMSC (unt) and fMSC with empty pLV (pLV) at week 0, 1, 2, and 3 in triplicate (total of 60 samples). Raw RNA-seq data were processed by the RNA-seq BioWDL pipeline pipeline version 5.0.0 developed by the SASC team at LUMC, LUMC, Leiden, the Netherlands).

  Dataset EGAD50000001839

• Tapestri Sequencing Data of PDAC Autopsy Samples

  This dataset comprises single-cell DNA sequencing data for selected pancreatic ductal adenocarcinoma (PDAC) autopsy samples. It employs a targeted gene panel to identify single nucleotide variants (SNVs) and copy number variations (CNVs) using the Mission Bio Tapestri platform. The samples encompass primary and metastatic tissue from selected PDAC patients. This dataset includes 74 sample-level BAM files and 24 patient-level H5 files, generated by the MissionBio pipeline.

  Dataset EGAD50000001936

• ERDERA WES reanalysis - DPF1 Batch 4

  This dataset comprises processed genomic data from 1063 samples, corresponding to 1063 whole-exome sequencing experiments. Data files include CRAM, gVCF (containing short variants, copy number variants, and structural variants), RoH (BED), B-allele frequencies (BW), and variant IGV visualizations (XML). Associated phenotypic and pedigree information for all samples is also included.

  Dataset EGAD50000002389

• TenK10K Phase 1: Whole Genome Sequencing tandem repeats multi-sample VCFs

  Tandem repeat variants were called for 1,925 samples from phase 1 of the TenK10K project. Variant calling from WGS alignments to the GRCh38 reference assembly was completed with ExpansionHunter v5. This dataset is comprised of autosomal tandem repeat variants provided as multisample compressed VCF format files. SNV-derived principal component scores used in the manuscript (Tanudisastro et al.) are also provided in this dataset.

  Dataset EGAD50000002378

• Single-Cell DNA and Protein Sequencing Data from a Pediatric UBA1-Mutated MDS Patient

  This dataset contains raw single-cell DNA and protein sequencing data (FASTQ files) generated from a pediatric patient diagnosed with UBA1-mutated MDS. Samples were collected at two clinical timepoints and processed using single-cell DNA and Protein sequencing technology. The dataset includes paired-end sequencing reads for all libraries. Data are provided under controlled access through the associated Data Access Committee.

  Dataset EGAD50000002372

• ERDERA WES reanalysis - DPF1 Batch 3

  This dataset comprises processed genomic data from 1243 samples, corresponding to 1243 whole-exome sequencing experiments. Data files include CRAM, gVCF (containing short variants, copy number variants, and structural variants), RoH (BED), B-allele frequencies (BW), and variant IGV visualizations (XML). Associated phenotypic and pedigree information for all samples is also included.

  Dataset EGAD50000002332

• ERDERA WES reanalysis - DPF1 Batch 2

  This dataset comprises processed genomic data from 733 samples, corresponding to 733 whole-exome sequencing experiments. Data files include CRAM, gVCF (containing short variants, copy number variants, and structural variants), RoH (BED), B-allele frequencies (BW), and variant IGV visualizations (XML). Associated phenotypic and pedigree information for all samples is also included.

  Dataset EGAD50000002331

• Somatic copy number alterations profiling in non-small cell lung cancer and their correlation with clinical efficacy in first-line treatment

  Genomic data from FFPE tumor samples of 258 patients with non-small cell lung cancer (NSCLC), profiled by shallow whole-genome sequencing (sWGS) at 1x. The study aimed to characterize somatic copy number alterations (SCNAs) and SCNA burden to assess their clinical relevance for patient stratification across different first-line treatments.

  Dataset EGAD50000002322

• Raw and processed snRNAseq data of Choroid Plexus Tumors

  This dataset contains raw sequencing and processed data of single nuclei transcriptomes. The data were generated with 10x chromium probe-based single-nucleus assay on FFPE tissues of 43 Choroid Plexus Tumour resections and 12 non-neoplastic fetal and adult ChP resections. Raw data contain BAM files of the sequencing. Processed data contain count matrices as generated by 10x CellRanger for raw and filtered running options.

  Dataset EGAD50000002320

• Single-cell RNA sequencing of Small Intestinal Neuroendocrine Tumors (SI-NET)

  Single-cell RNA sequencing (scRNA-seq) was performed on cells isolated from intestinal mucosa and small intestinal neuroendocrine tumors (SI-NETs) to compare their transcriptomic profiles. Tumor and adjacent normal tissues were collected from two SI-NET patients, enzymatically dissociated, and processed into single-cell suspensions. Single-cell libraries were generated using the Chromium Single Cell 3′ Reagent Kit v3 and sequenced on an Illumina platform to produce FASTQ files for downstream analysis.

  Dataset EGAD50000002265

• Bulk RNA sequencing of 36 multi-region IPMN–PDAC tumours comprising 160 sequencing runs

  This dataset contains bulk RNA sequencing data generated from 36 multi-region tumour samples obtained from patients with intraductal papillary mucinous neoplasms (IPMN) and associated pancreatic ductal adenocarcinoma (PDAC). A total of 160 sequencing runs are included. Libraries were prepared from poly(A)-selected RNA and sequenced on an Illumina platform. The data are provided as raw sequencing files for downstream transcriptomic analyses.

  Dataset EGAD50000002215

• ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A

  ZFHX4 as a transcription factor specifically induced during the in vitro differentiation of iPSC-derived mDANs. Depletion of ZFHX4 during neuronal differentiation led to a significant reduction in the number of mDANs while its overexpression did not lead to any changes in mDAN count. Identification of ZFHX4 target genes using CUT&Tag profiling and RNA-seq upon ZFHX4 knock-down (KD) revealed its involvement in cell cycle regulation during mDAN differentiation

  Dataset EGAD50000001605

• Small RNA-Seq of MicroRNA's in extracellular vesicles of Ushers Syndrome patients

  Small RNA-Seq dataset of MicroRNA's found in tear extracellular vesicles (EVs) and hiPSC-derived retinal pigment epithelium (RPE) cells of Ushers Syndrome patients and control samples. 14 samples were isolated and assessed for quality before preparing libraries using the miReasy and TruSeq Small RNA Library Preparation Kit. Sequencing was performed on the Illumina NextSeq 2000 platform, generating paired end FASTQ files.

  Dataset EGAD50000001709

• RNA-seq FASTQ files studied in Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application

  This data set contains 12 paired fastq files (RNA-seq) from one wild-type iPS cell, two HLA-KO iPS clones and three CD14+ monocytes differentiated from them. The RNA-seq libraries were generated with Illumina TruSeq Stranded Total RNA library prep kit. The libraries were sequenced with Illumina NovaSeq 6000 in paired-end mode.

  Dataset EGAD50000001700

• Human brain development single cell sequencing additional samples

  69 tissue samples from various parts of the developing human embryo brain were dissociated and single cells were collected and processed without bias for mRNA-seq using 10X chromium 3' protocol. Libraries were sequenced on Illumina NovaSeq and reads aligned against the human GRCh38 genome. This is an addition to EGAD00001006049 Human development single cell sequencing, consisting of samples added after the original submission to EGA, but included in final paper.

  Dataset EGAD50000001295

• MissionBio single cell DNA and protein seq for 2 samples

  This dataset contains MissionBio Targeted single-cell DNA and Protein sequencing data from a primary sample and a patient-derived xenograft (PDX) model, which is used to investigate the clonal evolution in the FOXF1/FENDRR ALL subtype. All the 2 samples are in bam file type.

  Dataset EGAD50000001793

• RNA-sequencing from ALL patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study.

  Dataset contains RNA-sequencing data (fastq files) from 45 patients treated on the the Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study, an MRD-stratified Paediatric Protocol. Patient samples (bone marrow or peripheral blood) were taken at diagnosis. mRNA was extracted from blast cells and underwent paired-end sequencing (75bp) using the illumina NextSeq platform. Genomic data was used for identification of genomic drivers of acute lymphoblastic leukaemia (ALL).

  Dataset EGAD50000001111

• WES analysis of DMD-ASD, DMD-ID and DMD-Control individuals for de novo and rare risk variants analysis

  This project generated a whole-exome sequencing (WES) dataset of 83 boys with a pathogenic variant in the DMD gene, along with WES data from the parents of 38 of them, totaling 159 samples. In addition to DMD, 12 boys also had ID (12 DMD-ID samples), 36 boys had ASD (DMD-ASD samples) and 35 did not present ID or ASD diagnosis (DMD-Control samples).

  Dataset EGAD50000001113

• Single cell data from TB patients

  The dataset comprises single-cell RNA sequencing (scRNA-seq) data derived from around 60,000 PBMCs collected from donors across different severity groups of extrapulmonary tuberculosis (EPTB) and healthy controls (3 healthy, 3 mild, 3 intermediate, 3 severe). The data include both transcriptomic and surface protein expression profiles obtained using the BD Rhapsody Single-Cell Multiomics System. Libraries were prepared for whole transcriptome analysis (WTA), AbSeq, and sample tagging, with sequencing performed on a NovaSeq 6000 system.

  Dataset EGAD50000001118

• WES of serrated polyposis syndrome

  Samples were obtained from patients diagnosed with serrated polyposis syndrome (SPS). To provide further detail, the dataset comprises two whole-exome sequencing samples from patients within the same family, uploaded in BAM file format with IDs 449758 and 449549. Exomic regions were sequenced using HiSeq2000 Platform (Illumina, San Diego, USA) and Sure SelectXT All Exon v5 kit (Agilent, Santa Clara, CA, USA) for exon enrichment. Only those potentially pathogenic germline genetic variants shared by both individuals were considered.

  Dataset EGAD50000001126

• RNAseq of pre- and post-5AZA-treated head and neck cancer patients refractory to anti-PD-1 therapy

  RNA sequencing (RNA-seq) was performed on baseline (before low-dose 5-aza treatment) and on-treatment (low-dose 5-aza treatment for 5 or 10 days) tumor samples from eight participants with head and neck cancer who were refractory to anti-PD-1 therapy. RNA library preparations, sequencing reactions, and initial bioinformatics analyses were conducted at GENEWIZ, LLC. In total, 16 150-bp pair-end RNAseq data were generated.

  Dataset EGAD50000001010

• Transcriptome analysis of patient-derived Schwann cells isolated from human sural nerve biopsies

  This dataset contains the transcriptome analysis of human Schwann cell cultures obtained from sural nerve biopsies from six patients with polyneuropathies (N=3/patient, totalN=18) as well as the nerve fascicles from where they were isolated (N=1/patient, totalN=6). In addition, this dataset includes 8 samples out of commercial human Schwann cell cultures and one sample of a fibroblast culture, which serve as controls for further analysis.

  Dataset EGAD50000001021

• Diagnostic yield and clinical utility of whole-exome sequencing in pediatric patients with rare and undiagnosed diseases in the Czech Republic

  In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. WES was implemented as a first-line test after inclusion in the study as part of the diagnostic workflow. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023.

  Dataset EGAD50000000640

• RNAseq from 6 organotypic co-cultures (OC cells bulk/OCSC with or without TME)

  The dataset contains samples of 6 organotypic co-cultures, assembled with patient-derived material from ovarian cancer (OC) patients. Tumor cells, both as bulk and as cancer stem cells-enriched (OCSC) populations, are cultured or not with in vitro peritoneal TME (for details see Battistini C et al, Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness, CDDis 2024). Dataset is composed by fastq file (paired end) type from bulk RNA-Seq.

  Dataset EGAD50000000523

• RNA sequencing of Ewing sarcoma and CIC-DUX4 sarcoma

  RNA sequencing of a collection of 6 Ewing sarcoma and 3 CIC-DUX4 sarcoma tumoroids plus 3 matched patient tumors. Tumoroids were established from digested patient tumor material as 3D culture in Matrigel. After 2-3 month of growth, RNA was isolated from individual tumoroid models using the RNeasy Kit (Qiagen) and used for whole exome sequencing. RNA from corresponding patient tumors was tested in parallel, if available.

  Dataset EGAD50000000557

• Clinical data and mapping file

  Patient demographic characteristics, treatment, and survival data for IMbrave151 (N = 162), with one patient per line. Mapping file to map anonymized subject IDs to RNAseq IDs

  Dataset EGAD50000000569

• Sex Differences in MAGEL2 Gene Promoter Methylation in High Functioning Autism - Trends from a Pilot Study Using Nanopore Cas9 Targeted Long Read Sequencing

  Using DNA extracted from peripheral blood, Cas9-targeted nanopore DNA sequencing was used to analyze MAGEL2 gene, including its entire regulatory construct (chr15:23639316-23651466), for sequence variation and 5-methyl-cytosine (5mC) modification in a cohort of adults with HFA compared to sex- and age-matched NC.

  Dataset EGAD50000000726

• Detection of a recently described pre-T cell receptor-alpha immunodeficiency exclusively using whole genome sequencing

  In this study, we describe the role of whole genome sequencing (WGS) in providing a definitive diagnosis for a child with T cell deficiency, where targeted panel sequencing of SCID genes and whole exome sequencing had failed. A novel homozygous 8kb deletion in PTCRA, encoding pTCR, was identified. WGS sequence data from the proband, proband’s mother, and proband’s father are deposited.

  Dataset EGAD50000000866

• Reconstructed VDJ sequences from Smart-seq2 data

  The dataset contains reconstructed VDJ sequences (fasta files) and accompanying metadata for each cell (csv file) from scRNA-seq data generated with the Smart-seq2 protocol. The VDJ sequences were reconstructed with the computational tool BraCeR using raw fastq files as input. The dataset contains sequences from 355 IgA+ peripheral blood B-lineage cells of two untreated celiac disease patients. The sequences comprise both IgA+ transglutaminase 2-specific and other IgA+ B cells.

  Dataset EGAD50000000341

• EED inhibition of organoid development

  Transcriptomics and epigenomics after chemical inhibition of EED during early human brain organoid development. To investigate the role of H3K27me3 inhibition during neuroectoderm induction, we treated brain organoids with 3 concentrations of EED inhibitor (and control) during the transition of pluripotency to neuroepithelium. At the neuroepithelium stage, we profiled the organoids using scRNA-seq (transcriptome) and bulk Cut&Tag (H3K27me3, H3K27ac). Library preparation for scRNA-seq was carried out with the 10x genomics platform.

  Dataset EGAD50000000224

• Profiling of gene expression and epigenomics in the fetal brain

  scRNA-seq and Cut&Tag from a sample of the human fetal brain. To compare neurogenesis in the primary human brain with that in organoids, we profiled transcriptome and chromatin accessibility (10X multiome) as well as bulk Cut&Tag of histone modifications H3K27me3, H3K27ac and H3K4me3. We used a human brain sample from GW 19 for all experiments.

  Dataset EGAD50000000225

• Dataset for Fragle Software Development and Evaluation

  Fragle is a deep learning based two stage model that quantifies ctDNA from blood plasma derived cfDNA bam files. Fragle was developed using some previously published datasets and some newly generated data. Fragle was evaluated using some validation cohorts and some unseen cohorts. Some of these cohorts are newly created consisting of total 365 low pass (2-3X) whole genome sequencing bam files mapped to hg19/GRCh37. This dataset contains these newly generated bam files.

  Dataset EGAD50000000167

• bfast CohortD clinical data

  Clinical data for BFAST Cohort D, including time-to-event, tumor response, and baseline prognostics data.

  Dataset EGAD50000000149

• bfast CohortD OSPL

  ctDNA sample data (one sample per line) for BFAST Cohort D including sample-level summaries like tumor fraction (cTF).

  Dataset EGAD50000000147

• PBMC all cell metadata

  Cell annotation for single cells of PBMC collected from 113 patients, including UMAP coordinates and annotation.

  Dataset EGAD50000000145

• CD8 T cell PBMC metadata

  Cell annotation for single CD8 T cells of PBMC collected from 113 patients, including UMAP coordinates and annotation

  Dataset EGAD50000000144

• Clinical data IMvigor130 cohort

  Clinical data for IMvigor130 cohort of patients, including treatment, response, survial time, and tumor PDL1-IC staining score.

  Dataset EGAD50000000143

• Expression array

  The whole study comprises of two patient cohorts. Screening cohort: 40 patients of Germany; validation cohort: 40 patients from Asia. Further, bile duct and CCA cell lines have been analyzed.
This dataset contains expression array data for 32 patients of the screening cohort with 8 of them having paired normal tissue plus an additional relapse tumor/normal pair of one of those 8 patients and a patient only with normal tissue. Data was generated on a HumanHT-12 v4 Bead Array (Illumina) and is stored in IDAT file format.

  Dataset EGAD00010002596