16792 results for "sec+and+unspecified+malignant+neoplasm"

in 38.58 milliseconds.

• cfRRBS on cfDNA from pediatric cancer

  In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining diagnostic challenges in pediatric oncology in a cost-effective and minimally invasive manner.

  Study EGAS00001004194

• Chordoma_Sequencing_Project_Whole_Genome

  This is a continuation of the Chordoma Sequencing Project, prelim #G0175-122-CF. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. The Chordoma Foundation will fund the RNA Sequencing/Methylation and SNP6 costs for this project while the whole genome and library sequencing will be covered under the CGP, 2012-2013 core WTSI internal funding. An additional sequencing of three cancer cell lines will be added to this work, financed by the Chordoma Foundation. In this project, the Chordoma foundation will pay for the additional costs of methylation, RNA Seq,

  Study EGAS00001000409

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• RNA_seq_of_Toxoplasma_gondii_response_in_human_macrophages

  Toxoplasmosis is a zoonotic disease caused by a ubiquitous protozoan parasite called Toxoplasma gondii, which caninfect all mammal and bird species throughout the world. seroprevalence varies widely between countries. Studieshave estimated that between 7-34% of people in the UK have been infected with T. gondii. The vast majority of thesepeople will not have noticed any symptoms, however about 10% of people develop a mild to moderate self limitingflu-like illness. Following the acute active stage of the infection the parasite persists in the body in the form of cysts,particularly in heart and skeletal muscle and nervous system tissues, for many years, and usually for life. Inimmunocompetent persons these cysts do not pose a health risk. We will use RNA-seq to quantify the transcriptionalresponse of macrophages to T gondii infection.This 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/

  Study EGAS00001001708

• Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

  Testicular germ cell tumor (TGCT) is the most common cancer in young men1,2. Here we aimed to identify novel risk factors for TGCT using whole-exome sequencing, which was performed on 328 affected individuals from 153 families, 634 sporadic cases and 1,644 controls. We searched for genes that were recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. 8.7% of families carried rare disruptive mutations in the cilia-microtubule genes (CMG) as compared to 0.5% of controls3 (P=2.1x10-8). The most significantly mutated CMG was DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumors from carriers. DNAAF1 as a cause of TGCT was supported by a DNAAF1Hu255h(+/-) zebrafish model with 94% penetrance for TGCT compared to 14% in wildtype fish. These data implicate cilia-microtubule inactivation as a cause of TGCT development and are the first evidence for CMGs as cancer susceptibility genes.

  Study EGAS00001001789

• Heritable pulmonary arterial hypertension in a large Iberian family

  Data from a study of a large Iberian family (n=65 subjects, 5 generations) affected by pulmonary arterial hypertension (PAH) and segregating with the BMPR2 missense mutation p.Arg491Gln (rs137852749, c.1472G>A). PAH is a rare disease characterized by an abnormal rise in mean pulmonary arterial pressure (> or equal to 25 mmHg at rest), which, in turn, leads to a progressive increase in pulmonary vascular resistance and ultimately to death, due to right ventricular failure. Heritable PAH has an overall prevalence below 1 case per million adults and is defined by either the presence of a known genetic defect linked to the disease or a positive family history. Heritable PAH is inherited as an autosomal dominant disease. However, not all BMPR2 mutation carriers develop the disease, highlighting the presence of reduced penetrance. In this family, there are 22 mutation carriers from which 8 were diagnosed with heritable PAH and the other 14 were healthy at the time of examination.

  Study EGAS00001003123

• FBSeq: RNA sequencing of human fetal brain.

  RNA sequencing of 120 human fetal brains (aged 12-19 post-conception weeks) was performed as part of a Medical Research Council (U.K.) funded project (MR/L010674/2) to investigate genetic effects on gene expression in the developing human brain and their role in neuropsychiatric disorders. Human fetal brain tissue from elective terminations of pregnancy was provided by the Human Developmental Biology Resource (HDBR) (http://www.hdbr.org), with ethical approval (#08/H0712/34), and with consent for use of fetal material for medical research provided by female donors. Total RNA was extracted from half of the available brain tissue from each fetus using Tri-Reagent and treated with TURBO DNase. RNA-Seq libraries were prepared using 1µg of purified total RNA and the Illumina TruSeq Stranded Total RNA Library Prep kit, following ribosomal RNA depletion. Libraries were sequenced on the Illumina HiSeq 2500 or HiSeq 4000 systems, generating at least 50 million read pairs per sample.

  Study EGAS00001003214

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Study EGAS00001001183

• Whole exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

  Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1-year of treatment or exceptional cases of complete response to trastuzumab for ≥ 10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NR)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P=0.07), while more significantly pronounced in copy number gains (P=0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within chr8 (P=0.02) and in chr17 (P=0.06) and conferred a statistically significant benefit in overall survival.

  Study EGAS00001004486

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Study EGAS00001004544

• UK renal cancer samples genotyped on Illumina OmniExpress BeadChip

  Renal cell carcinoma (RCC) cases comprised adult patients with histologically proven RCC were collected through two sources within the UK. First, 856 cases from SORCE, a MRC collection of surgically treated RCC cases ascertained through UK clinical oncology centres. Second, 189 RCC cases collected through the ICR and Royal Marsden NHS Hospitals Trust. Cases included 590 clear cell carcinomas (CCCs), 42 papillary carcinomas (PCs), 33 chromophobe carcinomas (CCs) and 19 mixed or other histological subtypes. DNA was extracted from EDTA-venous blood samples using the conventional methods and quantified using PicoGreen (Invitrogen). Cases were genotyped using the Human OmniExpress-12 BeadChip according to the manufacturer's recommendations (Illumina Inc, San Diego, CA, USA). After strict QC, 944 cases were retained. Data provided in plink format. Controls used were data from the Wellcome Trust Case Control Consortium 2 (WTCCC2) 1958 birth cohort and the UK Blood Service Control Group (available as EGAS00000000028).

  Study EGAS00001002336

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD_Full_STDY

  Following on from our pilot study we will investigate further the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. We will perform 15X whole-genome sequencing of crypts biopsied from patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. This 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/

  Study EGAS00001003249

• Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements

  Sparse profiling of CpG methylation in blood by microarrays have identified epigenetic links to common diseases. We apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal ~400), providing high-resolution methylation profiling (>1.3M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

  Study EGAS00001003415

• Natural history of clonal haematopoiesis (2017-09-04)

  The incidence of acute myeloid leukemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 60. Only 10-15% of cases evolve from a pre-existing myeloproliferative or myelodysplastic disorder; the remaining cases arise de novo without a detectable prodrome and are diagnosed upon development of bone marrow failure. Analysis of diagnostic blood samples has demonstrated that de novo AML is preceded by the accumulation of somatic mutations in pre-leukemic hematopoietic stem and progenitor cells (preL-HSPCs) that subsequently undergo clonal expansion. If individuals in this pre-leukemic phase could be identified, methods for determination of risk and monitoring for progression to overt AML could be developed. However recurrent AML mutations also accumulate during aging in healthy individuals who never develop AML, referred to as age related clonal hematopoiesis (ARCH). To distinguish individuals with preL-HSPCs at high risk of developing AML from those with ARCH, we undertook deep targeted sequencing of genes recurrently mutated in AML in blood samples from 133 individuals in the European Prospective Investigation into Cancer and Nutrition (EPIC) study taken on average 6 years before they developed AML (pre-AML group), together with 683 matched healthy individuals (Control group). Pre-AML cases displayed accelerated age-correlated accumulation of somatic mutations.The identity, number and variant allele frequency (VAF) of mutations differed between the two groups, and were incorporated into a computational model of AML risk prediction that accurately distinguished pre-AML cases from controls on average 7 years prior to AML development. Our findings provide proof of concept that early prediction of AML development is feasible in high-risk populations, paving the way for early disease detection, monitoring, and potentially prevention.

  Dataset EGAD00001003703

• Genetic Heterogeneity of the familial gastric neuroendocrine tumors (2018-06-06)

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. This 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/ . This dataset contains all the data available for this study on 2018-06-06.

  Dataset EGAD00001004153

• Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Study EGAS00001007650

• GENOMIC MUTATION LANDSCAPE OF SKIN CANCERS FROM DNA REPAIR-DEFICIENT XERODERMA PIGMENTOSUM PATIENTS

  Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis (TLS) DNA polymerase η (group V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyzed 38 skin cancer genomes from five XP groups. We found that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors revealed the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

  Study EGAS00001006732

• Whole genome sequencing of patients with or at risk for HCC

  Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

  Study EGAS00001007249

• Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia

  In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness, and poor patient outcomes. A later arrest was associated with lineage fidelity, deep and durable leukemia remissions, and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1+ pre-leukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI-efficacy is an unexpected outcome of the differentiation stage at which this leukemia transforms.

  Study EGAS00001007167

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant_TGS

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001005298

• Rare occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers

  Aristolochic Acids (AAs) are a family of carcinogenic phytochemical compounds commonly found in plants of Aristolochia and Asarum genus. Comprehensive genomic profiling of genitourinary and hepatobiliary cancers has highlighted the widespread prevalence of Aristolochic Acid (AA) signatures in cancer patients across parts of Asia, particularly in Taiwan. The aim of our study was to determine in Oro-Gastrointestinal Tract (OGITC) cancers, the prevalence, role and significance that AA plays as a driver of tumorigenesis as AA containing products are commonly administered orally. This would suggest a possible etiological relationship between cancers of OGITC. However, in this study the rarity of AA mutational signatures in OGITC suggests that AA is unlikely to drive carcinogenesis in OGITC through direct exposure. Our study is valuable to show that AA exposure is not an equal driver of tumorigenesis in different organs and represents an important piece of information in the field.

  Study EGAS00001005909

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant___Bait_set_2

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001005534

• Oncogenic cooperation in a human de novo T-ALL model

  We previously modelled T-cell acute lymphoblastic leukemia (T-ALL) by over-expressing four oncogenes (activated NOTCH1, LMO2, TAL1, and BMI1) in healthy human umbilical cord blood cells through lentiviral transduction (Kusakabe et al, Nat Commun 10, 2913 (2019). https://doi.org/10.1038/s41467-019-10510-8). We have now tested individual effects of the four oncogenes by transducing human cells with all possible combinations of one, two, three, and four oncogenes. We also tested the effects of additional known T-ALL oncogenes including HOXA9, LYL1, MEF2C, NXK2.1, TLX1, and TLX3. In addition to culture in vitro on OP9-DL1 feeders, we also injected transduced cells into immunodeficient NSG mice. We observed differing abilities of the various oncogene combinations to support growth in vitro and frank leukemia in vivo. This study includes RNA-seq data from samples of transduced cells cultured in vitro as well as cells harvested from clinically moribund mice after development of leukemia in vivo.

  Study EGAS00001006055

• Phase 1 CX-5461 Trial (Canadian Cancer Trials Group Trial IND.231)

  CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination (HR) deficient models. In this multicentre Phase Ib trial in patients with solid tumors, 40 patients were treated across 10 dose levels (50 - 650 mg/m2) to determine the recommended phase II dose (RP2D), and evaluate safety, tolerability, pharmacokinetics. Defective HR was explored as a predictive biomarker. CX-5461 was generally well tolerated, with a RP2D of 475 mg/m2 d1, 8 and 15 every 4 weeks, and dose limiting toxicities of phototoxicity. Responses were observed in 10% of patients, primarily in patients with defective HR (ORR 14%). Reversion mutations in PALB2 and BRCA2 were detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization showed this toxicity is related to the CX-5461 chemotype, independent of G4 synthetic lethality. These results establish clinical proof-of-concept for this first-in class G4 stabilizer.

  Study EGAS00001006173

• HSC_colony_many_years_post_allogeneic_bone_marrow_transplant___Bait_set_3

  This study looks at human donors and recipients of allogeneic blood & marrow marrow transplantation. Each transplant "pair" (donor & recipient) underwent the transplant procedure 10 -30 years prior to sampling - the majority for an underlying diagnosis of leukemia. We will perform whole-genome sequencing on tens to hundreds of single HSPC (haematopoietic stem and progenitor cell)-derived colonies per individual. We will infer the phylogeny of these cells (those from both donor & recipient within a pair) by analysing the somatically acquired mutations within each cell. The structure of the phylogeny will allow estimates of hitherto unknown parameters such as the number of HSCs that engraft long-term, the dynamics of the engraftment process on the HSC level, and the additional mutation burden acquired through the arduous transplant procedure. This TGS part of the study is used for assessing the contribution of clones to mature blood subsets, and better timing mutations relative to transplantation.

  Study EGAS00001006572

• Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

  These data relate to Abbosh et al 2023 'Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA'. Some patients were included in this work that were excluded from the other TRACERx 421 papers (Frankell et al and Al-bakir et al) often due to exclusion criteria in the TRACERx clinical trial. Reasons include partial contamination with C>A artefact mutational signature (CRUK0480 ,0490) which were included for ctDNA detection analyses using high confidence clonal mutations but not clonality analyses, incomplete resection at primary surgery (CRUK0291, 0234, 0230, 0387, 0622) and a concurrent oesophageal second primary cancer (CRUK0498). The primary tissue exome sequencing for these patients that were used in this study are included in this repository. Deep targeted sequencing of (median 200) tumour specific mutations in plasma for 1069 samples from 198 TRACERx patients are also included. Additional details related to these patients and samples can be found in the supplementary or data repositories from Frankell et al and Abbosh et al.

  Study EGAS00001006923

• Blood transcriptome profiling links immunity to disease severity in myotonic dystrophy type 1 (DM1).

  The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to a) ascertain if transcriptome changes were associated with increasing disease severity, as measured by the muscle impairment rating scale (MIRS) and b) es-tablish if these changes in mRNA expression and associated biological pathways were also observed in the Dystrophia Myotonica Biomarker Discovery Initiative (DMBDI) microarray dataset in blood (with equivalent MIRS/DMPK repeat length). The changes in gene expression were compared using a number of complementary pathways, gene ontology and upstream regulator analyses, which suggested that symptom severity in DM1 was linked to transcriptomic alterations in innate and adaptive im-munity associated with muscle wasting. Future studies should explore the role of immunity in DM1 in more detail to assess its relevance to DM1.

  Study EGAS00001006926

• Epigenetic landscape of mixed phenotype leukemias

  Leukemias with ambiguous lineage comprise a number of loosely defined entities, often without a clear mechanistic basis. Here, we investigated a group of such leukemias with a CpG Island Methylator Phenotype (CIMP), previously identified as CEBPA-silenced AML. Transcriptomics and epigenomics analyses revealed a hybrid myeloid/lymphoid epigenetic landscape, whereas genetic alterations were heterogenous. This suggests that CIMP leukemias are defined by their shared epigenetic profile rather than a common genetic lesion. Gene expression enrichment showed strong similarity with ETP-ALL and an early lymphoid progenitor cell of origin. Accordingly, integration of differential methylation and expression revealed widespread silencing of myeloid transcription factors (TFs), among which CEBPA was key for differentiation arrest. Hypermethylation also resulted in loss of CTCF binding, accompanied by a few changes in chromatin interactions involving critical TFs like KLF4. In conclusion, epigenetic dysregulation, and not genetic lesions, explain the mixed phenotype of a group of CIMP leukemias resembling ETP-ALL.

  Study EGAS00001007094

• Northern Ireland COhort for the Longitudinal study of Ageing

  The Northern Ireland COhort for the Longitudinal study of Ageing (NICOLA) is a representative sample of ~8,500 people from across Northern Ireland. The study, which was set up in 2012, aims to understand what it is like to grow older in Northern Ireland. • NICOLA has a strong focus on molecular biomarkers so there is complementary genetic, epigenetic and transcriptomic data available for a subset of individuals. • We inherit much of our DNA from our parents while a small amount of this material changes as we get older. In NICOLA we have 551,839 directly genotyped and 18,148,478 imputed Single Nucleotide Polymorphisms (SNPs) currently available for 2969 participants. • Summary statistics for the association of these gene polymorphisms with ~30 phenotypes were generated. • Epigenetics provides a link between our inherited DNA and environmental influences from a person’s diet, medication and lifestyle. NICOLA has the epigenetic quality controlled profiles of 1984 individuals arising from variations in DNA methylation at 862,927 genetic sites.

  Study EGAS00001007915

• Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

  We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB B-lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB B-lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

  Dataset EGAD00001011122

• Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

  Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy.

  Study EGAS00001004407

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation patterns and terminal sequences of cell-free DNA (cfDNA) are altered by nucleases and biological mechanisms in the blood of cancer patients. The cfDNA fragment-end composition recovered from low coverage WGS (<1 fold coverage) using a bespoke software (FrEIA) is aberrant in the plasma from cancer patient (n = 418, 655 samples) compared to controls (n = 117). As a standalone test FrEIA allows detection down to ~0.2% tumor fraction in vitro and in silico at 95% specificity, leading to a sensitivity of ~71% for detecting lung cancer (14/22 stage I-II, 27/38 stage III, 92/127 stage IV) and ~68% for detecting esophageal adenocarcinoma (26/44 stage II, 46/62 stage III). Additional cfDNA biological patterns can be combined with FrEIA increasing the diagnostic potential of low coverage WGS at minimal cost (mean AUROC = 0.96). Integrating multiple cfDNA biological signal augments the diagnostic performance of liquid biopsy.

  Study EGAS00001006142

• Sequencing data from MethylScan assay on plasma

  Machine learning models in biomedical research are often hindered by demographic imbalances in clinical datasets, leading to biased predictions that disadvantage minority populations. Existing bias correction methods face limitations in handling the heterogeneity of biomedical data and the complexity of demographic influences. Here, we present DeBias, a computational framework for mitigating demographic biases in high-dimensional biomedical datasets. DeBias eliminates bias-associated subspaces within the entire feature space using control samples and enables global bias correction across all features, effectively preserving disease-specific signals while minimizing demographic distortions. To demonstrate its effectiveness, we applied DeBias to cfDNA methylation data for cancer detection. It achieved a >6-fold reduction in the number of features containing biases and outperformed existing methods in improving the cancer detection performance for minority populations. Our method represented a promising step toward developing machine learning models that are more accurate, reliable, and equitable for minority populations.

  Study EGAS00001008127

• Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile

  The Multiple Myeloma Research Foundation (MMRF) CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) trial (NCT01454297) is a longitudinal observation study of 1000 newly diagnosed myeloma patients receiving various standard approved treatments that aim at collecting tissue samples, genetic information, Quality of Life (QoL) and various disease and clinical outcomes over 10 years.

  Study phs000748

• High-throughput single-cell DNA sequencing of acute myeloid leukemia tumors with droplet microfluidics

  We developed a novel microfluidic platform to automatically barcode genomic DNA from individual cancer cells. Using this approach, we sequenced acute myeloid leukemia (AML) tumors targeting up to 62 loci relevant for the disease from thousands of cells. We predict that our platform will enable analysis of heterogeneity in AML and improve stratification and therapy selection.

  Study phs001627

• Characterization of Sex Differences in Human Placentas

  Whole exome and whole transcriptome sequencing data from human (Homo sapiens) placenta and maternal decidua tissues. This study characterizes sex differences in gene expression in the placenta. Differences in gene expression in maternal decidua from pregnancy with a male or female placenta. Patterns of X chromosome inactivation in the placenta. Genome-wide allele-specific expression in human placentas. 

  Study phs002240

• RNA Sequencing of ECOG-E1308

  This study reports the RNA sequencing of HPV positive oropharyngeal squamous cell carcinoma samples from patients with HPV-associated stage III or stage IV cancer of the oropharynx that was surgically resectible. These patients participated in the ECOG-E1308 trial, a phase II trial that studied paclitaxel, cisplatin, and cetuximab followed by cetuximab and two different doses of intensity-modulated radiation therapy.

  Study phs003320

• National Cancer Institute (NCI) Waldenstrom Macroglobulinemia Genome-wide Association Study

  A discovery GWAS is performed, consisting of genotyping 221 Waldenstrom macroglobulinemia (WM) cases on the Illumina Omni Express 12v1.1 platform and analyzing the genotypes together with those of 3798 previously genotyped controls in a model taking into account gender, age, and principal components of ancestry (i.e., significant eigenvectors). Directly genotyped data are supplemented by imputation using the Haplotype Reference Consortium.

  Study phs001284

• Gene Expression Analysis in Clonal Evolution of Fanconi Anemia

  We examined hematopoietic progenitor cells derived from iPSCs from patients with Fanconi anemia, including bone marrow failure cells (FANCA-/- HPCs), 'healthy', complemented cells (FANCA-/- cells with a wild-type FANCA cDNA), MDS-like cells (FANCA-/- HPCs with introduced mutations in RUNX1 and other MDS-associated genes), and Fanconi AML-like cells ('FAL'; MDS-like cells expressing FLT3-ITD).

  Study phs003024

• Myocardial Infarction Genetics Exome Sequencing Consortium: Ottawa Heart Study

  The Ottawa Heart Study is a cross-sectional case-control study designed to identify genes that predispose to angiographically defined coronary artery disease. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000806

• The Genomic Complexity of Primary Human Prostate Cancer

  Seven primary prostate cancers and their paired normal counterparts were DNA-sequenced on a massively parallel sequencing platform. This approach was taken to investigate the genomes for mutations and genomic alterations that would be undetectable by lower-resolution methods. As result, tumors containing chains of balanced rearrangements that occurred within or adjacent to known cancer genes were discovered.

  Study phs000330

• Genetic Determinants of Susceptibility to Severe COVID-19 Infection

  The goal of the project is to identify genetic susceptibility variants associated with acute COVID-19 infection susceptibility and severity using whole genome sequencing. The target of the project will include WGS data from whole blood samples of up to approximately 2000 COVID-19 patients (including critical/severe patient subgroup, asymptomatic/mild subgroup) from domestic and international medical institutions.

  Study phs002245

• MDD2000AFFY

  Sub-study QI: 941 cases of Major Depressive Disorder (MDD) from the Queensland Institute of Medical Research (QIMR), Australia Sub-study VU: 127 MDD cases from The Netherlands Study of Anxiety and Depression (NESDA) (http://www.nesda.nl) and The Netherlands Twin Registry (NTR) (http://www.tweelingenregister.org) based at the VU Amsterdam, The Netherlands. Sub-study ED: 373 MDD cases from the University of Edinburgh, UK.

  Study phs000658

• Molecular Analysis of Alliance A031201 Study

  This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

  Study phs003717

• Exome Sequencing in an Ancestrally Diverse Autism Cohort

  Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders manifested by impaired social communication, repetitive behaviors, and restricted interests. We performed whole exome sequencing (WES) on a total of 754 individuals from 195 families, including 222 probands with ASD, from diverse ancestral backgrounds. We identified potentially pathogenic variants in known and novel ASD or neurodevelopmental disease genes.

  Study phs003603

• Identifying the Genetic Basis of Variably Protease-Sensitive Prionopathy (VPSPr)

  Design: Sequencing of cases onlyMolecular technologies: Exome sequencing and custom targeted sequencing of PRNPAims: Identify modestly penetrant, high odds ratio variants conferring risk of variably protease-sensitive prionopathy (VPSPr)Population: n=67 autopsy-confirmed VPSPr cases, United States, 1997-2021Principal findings: Association to PRNP M129V replicated, no other causal variants identifiedData available: Raw sequencing data and metadata

  Study phs004012

• Comprehensive survey for the construction of an integrated database of food, gut microbiome, and health information (the "Sukoyaka Health Survey") A data collection study exploring the relationship between the gut microbiome, food, health, and the genome.

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 51 healthy Japanese. We analyzed some participants living in Nagahama. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome were analyzed.

  Study JGAS000680

• The Adhesion GPCR ADGRL2 Engages Galpha13 to Enable Epidermal Differentiation

  We sought to determine the role of ADGRL2 in epidermal homeostasis. Primary neonatal foreskin keratinocytes were obtained from discarded surgical samples at a California hospital. Samples were anonymous and not selected. ADGRL2, working through GNA13, was found to promote epidermal differentiation through the ADGRL2 intracellular loop 3 (ICL3) loop, using the methods of RNA-seq and Perturb-seq.

  Study phs004223

• Whole blood transcriptomics analysis in Antiphospholipid syndrome in patients with Systemic Lupus Erythematosus

  We analyzed whole-blood RNA-sequencing data from 299 SLE patients (108 SLE-aPL-positive, including 67 SLE-APS; 191 SLE-aPL-negative) and 72 matched healthy controls (HC). Pathway enrichment analysis, unsupervised WGCNA analysis and machine learning were applied to distinguish disease endotypes. Deconvolution analysis was performed to characterize the peripheral blood immune cell profile.

  Study EGAS00001007750

• Microarray genotyping of idiopathic hypersomnia patients (11 orexin mutation-positive patients, 85 orexin mutation-negative patients)

  We performed a principal component analysis (PCA) to determine whether population stratification or differences in the genetic background are present between the orexin mutation-positive and -negative idiopathic hypersomnia groups. Genome-wide single nucleotide polymorphism (SNP) data in patients with idiopathic hypersomnia (orexin mutation-positive patients and orexin mutation-negative patients) were utilized for the PCA.

  Study JGAS000508