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• Tandem DNA Repeats Activate hTERT Gene Transcription

  Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell and chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of E-boxes, cooperated with the proximal promoter in hTERT regulation by bHLH transcription factors and maintained hTERT expression during embryonic stem cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations.  To assess the genetic polymorphism of VNTR2-1 in human populations, we analyzed genomic DNA samples of Caucasian Americans and African Americans enrolled in the Georgia Centenarian Study.  VNTR2-1 in these genomic DNA samples were PCR amplified and subjected to sequencing analysis usinb the PacBio® SMRT method. The result showed that all VNTR2-1 alleles in Caucasian Americans contained 76 or more 42-bp repeats, whereas 32% of VNTR2-1 alleles in African Americans had fewer than 76 repeats.  

  Study phs002428

• PIEZO1 Loss of Function Compound Heterozygous Mutation in the Rare Congenital Human Disorder Prune Belly Syndrome

  Prune Belly Syndrome (PBS) is a rare congenital myopathy that is incompletely understood genetically. In this IRB approved study, one white Non-Hispanic 35 year-old male PBS proband was prospectively enrolled and phenotyped. Blood lymphocyte DNA from the proband underwent paired-end Whole Exome Sequencing using the Illumina SureSelect kit and HiSeq2500 sequencer with data pipeline analysis. We aligned the subject's sequence against the GRCh38/hg19 assembly and variant calling was performed using data training sets from the 1000 Genomes Project, Omni 2.5 M SNP microarray, and HapMap phase 3.3. These variants were filtered for rare minor allele frequency ( 0.9, CADD score > 20, GERP > 4, MutationTaster = “DC”, Mutation Assessor = “M” or “NE”, and Vest > 3.00. Rare and novel candidate functional variants were screened in the ClinVar database for prior association with smooth muscle myopathy (SMM). Only variants that met these criteria were included for further analysis. Confirmed variants had inheritance analysis performed on available samples. Our WES analysis identified novel compound heterozygous variants in the PIEZO1 gene. We conducted an extensive functional analysis of the PIEZO1 PBS variants that revealed loss-of-function characteristics. Thus, PIEZO1 mutations may be causal for PBS. Our WES data will be available through dbGaP.

  Study phs003475

• DEMENTIA-SEQ: WGS in Lewy Body Dementia and Frontotemporal Dementia

  Lewy body dementia, amyotrophic lateral sclerosis/frontotemporal dementia, and multiple system atrophy are age-related, neurodegenerative syndromes that are poorly understood. Delineating the genetic risk that is driving the pathophysiology of these neurological diseases is fundamental for understanding disease mechanisms and for developing disease-modifying treatments. In version 1 of the study/dbGaP deposition, we performed a whole-genome sequencing study consisting of 7,403 total samples, including 2,633 genomes from patients with Lewy body dementia, 2,641 frontotemporal dementia patients, and 1,980 neurologically healthy controls. Of these, 6,907 were uploaded to dbGaP as the basis of the DementiaSeq, phs001963 dataset. The data relating to these samples are available on dbGaP. In version 2 of this study/dbGaP deposition, we made much of these data available on Anvil. More specifically, data for 6,254 of these samples were also uploaded to the ALS Compute platform on AnVIL. The data for the remaining 653 samples are only available on dbGaP. The dbGaP/AnVIL Table lists the availability of dbGaP and AnVIL for each individual sample: phd008475.In version 3 of the study/dbGaP deposition, we added whole-genome sequence data generated using DNA samples obtained from 683 patients diagnosed with multiple system atrophy.

  Study phs001963

• Joint-Specific TF Regulation in RA

  The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated bulk, whole-genome transcriptomic and chromatin accessibility data from FLS. Samples were matched in age, sex, and were homogeneous in that all had significant joint damage with longstanding disease requiring surgical intervention. Analysis revealed joint-specific patterns of FLS phenotypes, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF-stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an ‘activated' state relative to the ‘resting' state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

  Study phs003633

• Pre-Existing Skin-Resident CD8 and γδ T Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy

  Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immunotherapy. Here, we attempted to identify novel predictive biomarkers of response through extensive and deep multi-omics interrogation of 186 samples from 116 patients. We collectively integrated bulk RNAseq, single-cell RNAseq, multiplex immunofluorescence, and spatial transcriptomics. Importantly, we were also able to study 14 matched pairs of tissue samples from pre- and post-immunotherapy. In non-responders, tumors show evidence of increased tumor cell cycling, expression of neuronal stem cell markers, and IL-1α/β. Responders have evidence of increased type I/II interferon signatures and evidence of pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of multiple T cell receptors. Spatial transcriptomics demonstrated higher co-localization of T cells with B and dendritic cells in responders, with evidence of expression of chemokines important for co-stimulation. Finally, immunotherapy increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors in responders, further underscoring their therapeutic importance. These data identify potential novel actionable biomarkers and therapeutic targets for MCC.

  Study phs003629

• Chronic Renal Insufficiency Cohort (CRIC) - GWAS

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. Data available at dbGaP include genotype data for 3527 participants released in version 1. Plasma metabolomics and plasma proteomics data will be available at dbGaP in "Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP. More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at http://cristudy.org/Chronic-Kidney-Disease/Chronic-Renal-Insufficiency-Cohort-Study/bibliography-2024-2023.

  Study phs000524

• Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

  Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. This effect was lost with myeloid- or T-cell restricted Tet2 inactivation, or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, we demonstrate that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

  Study EGAS50000001191

• Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.

  Long expansions of short tandem repeats (STRs); i.e., DNA repeats of 2-6 nucleotides, are associated with some genetic diseases. Cost-efficient high throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads. We propose ab initio procedures for sensing and locating long STRs promptly by utilizing the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in eleven SCA31 samples using SMRT? sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution, and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads.

  Study JGAS000002

• Genomic and Genetic Analysis of Brain Tumors and Analysis of Their Clinicopathological Significance

  The treatment outcome of glioma patients remains disappointing, and more studies are needed to improve therapeutic strategies. In particular, it is crucial to understand the mechanisms underlying resistance to treatment and malignant transformation, as well as the intratumoral heterogeneity and interaction of tumor cells and host immunity. Recent advances in omics analysis techniques, such as next-generation sequencing (NGS), have enabled us to obtain omics data more easily and accelerated our ability to integrate this information and precisely characterize cases. In our project, we have already collected more than 100 pairs of human glioma/normal tissue samples, of which some are multiple specimens collected from initial and recurrent tumors, and some include multiple specimens collected from different regions within a single tumor. We used our in-house algorithms, composed of alignment and variant calling programs, to analyze omics data from multiple platforms, such as whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array, with our original cohort of glioma patients. Using several informatics tools, the information about genetic and epigenetic status and expression signatures were analyzed. Those data are expected to provide key information for investigating the mechanisms discussed above. Through this project, we hope to improve strategies for personalized therapy based on comprehensive omics data.

  Study JGAS000004

• Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers

  Metastasis formation is classically considered a late-stage event in colorectal cancer (CRC) evolution. Yet, the time and patterning by which metastatic competence is acquired remain poorly understood. Here, we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of CRC, concurrent with invasive front formation. However, while necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting additional bottlenecks like immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumor progression stages within individual early-stage CRCs. Whole-genome sequencing and growth factor-dependency assays exclude tumor cell-intrinsic acquired traits. In contrast, single-cell spatial atlases of the tumor-microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts (CAFs) to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid co-cultures confirm that these trophocyte-like CAFs induce plastic transitioning to oncofetal states. Thus, interactions between tumor and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during CRC progression.

  Study EGAS50000001532

• Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

  Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled a total of 697 OC tumour samples (566 primary and 131 recurrent including 69 patient-matched samples) from 595 patients of five independent multi-institutional cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant progression after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic landscapes of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through COX/PGE2 signaling upregulation. Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the BRCA-dependent crosstalk between dissimilar myeloid cells and TILs. We propose new targets to modulate the malignant and TAM compartments which improve efficacy of standard of care chemotherapy in mouse OC models with HR deficiency.

  Study EGAS50000001069

• Characterizing microbiome-directed fibre snacks in gnotobiotic mice and humans

  Knowledge of the interrelationships between what we eat and the configurations of our gut microbial communities is providing important insights into how food components that are not directly metabolized by human enzymes are linked to our physiology and health status. Changing food preferences brought about by Westernization that have deleterious health effects1,2, plus rapid population expansion, ongoing challenges to sustainable agriculture, and other forces contributing to increased food insecurity, are catalyzing efforts to identify more nutritious and affordable foods3. The gut microbial community is complex, dynamic, and exhibits considerable intra- and interpersonal variation in its composition and functions. The massive number of potential interactions between its components makes it challenging to define the mechanisms by which food ingredients affect community properties. There is also a paucity of information about the ‘bioactive’ ingredients of foods that influence the fitness and expressed functions of community members. Here, plant fibres, from different sustainable sources and targeting distinct features of obese human gut microbiomes in gnotobiotic mice, were formulated into snack prototypes and used to supplement controlled diets consumed by overweight and obese adults; the results revealed fibre-specific changes in their microbiomes that were linked to changes in their plasma proteomes indicative of altered physiologic state.

  Study EGAS00001005268

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal

  he Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003774

• Botswana 15 autosomal unlinked microsatellites

  Population structure was investigated in 990 Botswana individuals according to ethno-linguistics, Bantu and Khoisan, and geography (the nine administrative districts) using the AmpFLSTR Identifiler autosomal microsatellite markers. Genetic diversity and forensic parameters were calculated for the overall population, and according to ethno-linguistics and geography. The overall combined power of exclusion (CPE) was 0.9999965412 and the combined match probability 6,28 x 10-19. CPE was highest for the Khoisan Tuu ethnolinguistic group and the Northeast District at 0.9999582029 and 0.9999922652 respectively. CMP ranged from 6.28 x 10-19 (Khoisan Tuu) to 1,02 x 10-18 (Northwest district). Using pairwise genetic distances (FST), analysis of molecular variance (AMOVA), factorial correspondence analysis (FCA), and the unsupervised Bayesian clustering method found in STRUCTURE and landscape genetics software TESS, ethno-linguistics were found to have a greater influence on population structure than geography. FCA showed clustering between Bantu and Khoisan, and within the Bantu. This Bantu sub-structuring was not seen with STRUCTURE and TESS, which detected clustering only between Bantu and Khoisan. The patterns of population structure revealed highlight the need for regional reference databases that include ethno-linguistic and geographic location information. These markers have important potential for bio-anthropological studies as well as for forensic applications.

  Study EGAS00001002380

• WGS of 32 paired SRCC samples

  Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however with no systematical investigation for prognostic genomic features. We systematically investigated the clinical characteristics of 1,868 Chinese gastric cancer patients, and found that signet-ring cell content was significantly related to multiple clinical characteristics and treatment outcomes. Next, we performed whole genome sequencing for 32 SRCC patients with > 80% signet-ring cells in tumor, and identified frequent5 CLDN18-ARHGAP26/6 fusion (25%). With additional 797 patients for validation, we notice that prevalence of CLDN18-ARHGAP26/6 fusion is positively associated with signet-ring cell content (P = 4.1 x 10 -9 ), younger age at diagnosis (P = 4.2 x 10 -10 ), female/male ratio (P = 1.7 x 10 -9 ), and advanced TNM stage (P = 1.7 x 10 -5 ). Importantly, patients with CLDN18-ARHGAP26/6 fusion had a worse survival outcomes (P = 0.03), and got no benefit0 from platinum/fluoropyrimidines based chemotherapy (P = 0.92) compared to fusion-free patients (P = 0.001), which is consistent with the fact of oxaliplatin/fluoropyrimidine resistance acquired in CLDN18-ARHGAP26 introduced gastric cancer cell lines. Overall, this study provides new insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

  Study EGAS00001002668

• Summary statistics from genome-wide association study in glioma of 12,488 cases and 18,169 controls.

  Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,488 cases and 18,169 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  Study EGAS00001003372

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__Colorectal_LCM

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003455

• Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients

  Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.

  Study EGAS00001003689

• The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

  Molecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

  Study EGAS00001004518

• Nanopore_and_Illumina_sequencing_of_human_glioblastomas

  Liquid biopsy analysis refers to methods designed to detect tumour-specific material (e.g., circulating tumour cells or tumour DNA) in body fluids, such as urine or blood samples. A widely-used liquid biopsy approach consists of genotyping the circulating tumour DNA (ctDNA) through sequencing of plasma/serum DNA. Although useful in the context of metastatic disease (where the concentration of ctDNA is high), current liquid biopsy technologies show limited sensitivity of detection for the early detection of cancer, and low specificity, as cancer-related mutations accumulate in healthy tissues as part of the ageing process, thus making it difficult to distinguish these from tumour mutations, and because sequencing errors and true mutations show overlapping profiles. Therefore, developing liquid biopsy protocols with increased sensitivity and specificity represents an urgent clinical need. Here we harness extrachromosomal circular DNA (eccDNA) elements, which are circular DNA structures physically separated from the chromosomes of up to several Mbp long pervasive in human cancers, for liquid biopsy analysis. In this pilot study we will focus on the analysis of glioblastomas, because there is strong evidence for the presence of eccDNA in these tumour types, and because developing liquid biopsy approaches for brain tumours to reduce the invasiveness of brain tumour biopsies remains an unmet clinical need.

  Study EGAS00001005812

• RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

  To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

  Study EGAS00001004798

• Proteogenomics of chronic lymphocytic leukemia

  Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling. This is the transcriptomics data of the discovery cohort.

  Study EGAS00001005746

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma___2

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001003542

• Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

  SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P=3.2 x 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the Wuhan and Alpha-variant waves compared to non-carriers (HR 0.63, 0.42-0.93, P=0.02). We identify a distinct S-derived peptide that is predicted to bind effectively to HLA-DQB1*06 compared to other equivalent alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days post first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

  Study EGAS00001006909

• Swarm Learning to identify COVID-19, tuberculosis and leukemia patients based on blood transcriptomes

  Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis or COVID-19 is an important goal of modern precision medicine. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. We have recently illustrated that classical machine learning can identify leukemia patients based on their blood transcriptomes. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, artificial intelligence (AI), blockchain and privacy protection without the need for a central coordinator thereby going beyond federated learning. To illustrate its feasibility, using more than 12,000 transcriptomes from peripheral blood mononuclear cells and more than 2,000 peripheral blood transcriptomes we demonstrate that SL of omics data distributed across different individual sites leads to disease classifiers that outperform those developed at individual sites. Yet, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.

  Dataset EGAD00001006231

• NIPT samples for systematic evaluation of NIPT aneuploidy detection software tools

  This dataset contains two sets of samples. The reference sample set consists of a total of 669 samples that had been reported previously to be euploid by the NIPTIFY screening test. The validation sample set is based on a previously published validation study by Zilina et al. (1), consisting of 423 samples, of which 259 were high-risk pregnancies that had undergone diagnostic invasive prenatal analysis (1). All samples were sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously (1). This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#315/T-13). 1. Zilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing non‐invasive prenatal testing in the Estonian public health setting. Prenat Diagn [Internet]. 2019 Dec 6;39(13):1262-8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pd.5578

  Dataset EGAD00001007712

• Genetic drivers of epigenetic and transcriptional variation of human immune responses to infection (RNA-seq, ATAC-seq and ChIPmentation)

  RNA-seq, ATAC-seq and ChIPmentation data from monocyte-derived macrophages that were infected with Influenza A virus strain PR8WT, or a matching non-infected control.

  Dataset EGAD00001008422

• Pooled scRNA-seq of iPSC-derived neural stem cells from ADHD and control individuals

  This dataset comprises paired-end FASTQ files from single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed from somatic cells (keratinocytes, PBMCs, or lymphoblastoid cell lines) collected from individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) and age-matched healthy controls (ages 6–18 years). Reprogramming was carried out using the non-integrative Sendai virus system (CytoTune-iPS 2.0, Thermo Fisher Scientific), introducing OCT3/4, SOX2, KLF4, and cMYC. iPSCs were cultured in Essential 8 medium on vitronectin and underwent rigorous quality control including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping (Illumina Global Screening Array). NSCs were generated using a standardized neural induction protocol and validated via qRT-PCR and immunostaining for markers including PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Two independent scRNA-seq multiplexed experiments were performed: Experiment 1 (ADHD: n = 7; Control: n = 6) and Experiment 2 (ADHD: n = 9; Control: n = 7). Samples were pooled and demultiplexed using the Ensemblex algorithm, incorporating prior genotype data. After quality control filtering (>500 unique RNA molecules per cell), 30,433 single-cell transcriptomes were retained. Differential gene expression analysis was conducted to identify transcriptional signatures associated with ADHD compared to controls.

  Study EGAS00001008169

• Patient-derived pediatric brain tumor organoids faithfully recapitulate primary tumors

  Extensive molecular analysis by many groups has revealed a heterogeneous landscape of embryonal brain tumors, including medulloblastoma (MB) and atypical teratoid/rhabdoid tumor (ATRT). MB, the most common malignant pediatric brain tumor, is comprised of four molecularly distinct subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3), and Group 4 (G4). Among these, MB-SHH harboring MYCN amplification and TP53 mutation and MB-G3 with MYC overexpression or amplification constitute the most aggressive tumors, have the poorest clinical outcomes, and lack effective therapeutic options for recurrent disease. Here we describe the establishment of tumor organoid (TO) models from patient-derived orthotopic xenografts (PDOX) of MYCN-amplified and TP53-mutant MB-SHH, MYC-amplified MB-G3 and two ATRT which all grew in mice when reimplanted into the cortices of naïve recipient animals (TOX). Methylation, bulk and single-cell RNA sequencing, and whole genome sequencing demonstrated that TOs and TOXs faithfully recapitulated the molecular landscape and heterogeneity of PDOXs and primary patient tumors compared to established cell lines. The development of TOs will facilitate in vitro high-throughput drug or CRISPR screens without the need for use tumor-bearing mice. This will also accelerate the identification and validation of new vulnerabilities and in vivo preclinical testing toward clinical trials.

  Study EGAS00001008305

• MutWP1__CRUK_Grand_Challenge_Mutographs_of_Cancer__clear_cell_renal_cell_carcinoma

  The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development.

  Study EGAS00001002608

• Caregiving as a Natural Stressor in Studies of the Role of Genes That Affect Serotonin Function in Regulating Risk Factors for Coronary Heart Disease (CAREGIVER)

  The burden of caregiving for an ill relative has been shown to interact with existing comorbidities to increase risk of several health outcomes including metabolic syndrome and blood pressure reactivity. The CAREGIVER study was developed to compare cardiometabolic risk factors in caregivers and controls. These risk factors include physiologic measures, psychologic measures, neighborhood characteristics, and genetic and genomic factors. DNA and plasma were collected and used for examination of cardiometabolic and stress biomarkers, genotyping and methylation analysis.

  Study phs001747

• scRNA-seq of human follicular lymphoma and lymph node

  Cryopreserved cells from human nodal follicular lymphoma and lymph node samples were thawed and processed for scRNA-seq analysis. CD3+ CD19− 7-AAD− live T cells (six FL samples from the Original cohort) or 7-AAD− whole live hematopoietic cells (five lymph node and nine FL samples from Validation cohort 1) were sorted using a FACS Aria II or III instrument (BD Biosciences). To generate single-cell emulsions, 6,000–10,000 live cells were loaded into the 10X Genomics Chromium Controller for single-cell partitioning, along with the reverse transcriptase reagent mixture and 3' or 5' gel beads. Sorted T or whole hematopoietic cells were converted to barcoded scRNA-seq libraries using 10X Genomics Chromium single cell 3' reagent kits (v3) for the Validation cohort 1, 5' reagent kits (v1) for the Original cohort, according to the manufacturer’s instructions. The libraries were sequenced on an Illumina HiSeq X Ten or NovaSeq X Plus system, mapped to the human genome (build GRCh38), and demultiplexed using CellRanger pipelines (v3.1.0, 10x Genomics).

  Dataset EGAD50000001143

• SUM-seq data for spontaneously differentiated iPSCs to EBs

  Clonal CRISPRi/a hiPS cell lines were plated to induce spontaneous differentiation in KSR medium (KSR medium: knockout DMEM/F12 (Gibco, 12660012), 2 mM GlutaMAX, 1× NEAAs, 20% knockout serum replacement (Gibco, 10828010) and 0.1 mM β-mercaptoethanol (Merck-Millipore)). non-TC plates and dishes were used. At the day of plating, KSR medium was supplemented with Y-27632 (10 µM). The next day, medium was replaced with fresh KSR medium. Medium changes were performed every other day. EBs were transferred to 15 ml conical tubes and allowed to sediment at room temperature for 5 min. The supernatant was replaced with fresh KSR medium and cells were transferred onto non-TC treated plates and maintained at 37 °C, 5% CO2. On day 12 of differentiation, the KSR medium was replaced with Essential 6 medium (Gibco, A1516401). EBs were collected and subjected to SUM-seq library preparation as described in Lobato-Moreno et al. 2025 Nature Methods.

  Dataset EGAD50000001589

• Characterization of a New Case of XMLV (Bxv1) Contamination in the Human Cell Line Hep2 (Clone 2B) Using High-Throughput DNA- and RNA-Seq

  We have sequenced DNA and RNA from the Hep2 (clone 2B) cell line (Sigma-Aldrich catalog number: 85011412-1VL) using short read Illumina sequencing. We show that this cell line is indistinguishable from the HeLa cell line (as mentioned on the Sigma-Aldrich website) by mapping integrations of the human papillomavirus 18. We also show that the cell line is contaminated by the Bxv1 xenotropic murine leukemia virus. This contamination has to be taken into account when using the cell line in future experiments.

  Study phs001944

• 16S rRNA gene V4 region sequencing data, ASV profiles, and sample metadata of human faecal samples predominantly from the Estonian population

  This dataset comprises 16S rRNA gene V4 region amplicon sequencing data generated from 1,826 human faecal samples, predominantly from the Estonian population. The dataset includes raw sequencing reads and processed amplicon sequence variant (ASV) outputs, consisting of ASV abundance tables, representative ASV sequences, and taxonomic assignments. In addition, a sample metadata table is provided, containing sample and host information, including sample identifier, sequencing run identifier, date of sampling, sex, age, height, weight, nationality, disease status, and Bristol stool type. Sequencing was performed using the Illumina MiSeq and iSeq 100 platforms. The cohort includes individuals with no reported disease (n = 889), gastrointestinal diseases (n = 217), allergies and asthma (n = 194), thyroid gland disorders (n = 117), cardiovascular diseases (n = 103), various general health conditions (n = 139), cancer (n = 28), diabetes (n = 20), gynaecological issues (n = 7). Disease status was unavailable for 112 samples.

  Dataset EGAD50000002306

• Impact of Mutated CTCF DNA binding sites of Topologically associating domains on nearby Cancer Gene Regulation: A Multi-Omics Analysis

  Cutaneous squamous cell carcinoma (cSCC) is the most common lethal malignancy world-wide. Due in most part to the extremely high mutational burden (TMB) in cSCC, making sense of it’s non-coding and regulatory regional genomic variation has lagged that of other far less common cancers. This study presents the first investigation of mutations at CCCTC-binding factor binding sites (CTCFbs) of Topologically associating domains (TAD) across defined cSCC progression stages—primary non-metastatic (PNM), primary metastat-ic (PM), and lymph node metastasis (LNM).

  Study EGAS50000001686

• Identification of fusion transcripts by RNA-sequencing and Whole genome sequencing of a METABRIC patient sample

  Fusion transcripts and their exact breakpoints were identified in RNA-seq data (30X) of an ER-,HER2+ breast cancer. DNA-level breakpoints associated with the fusion events were determined by analyzing whole genome sequencing (WGS) data (30X) from the same donor. The RNA-seq and WGS data for this case were generated on the Illumina platform using standard protocols. The patient (MB-0152) derives from the METABRIC cohort for which array based copy number and gene expression data were previously described (EGAS00000000083).

  Study EGAS00001002475

• RUNX1 mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

  We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1 mutated FPD-MM families. Genomic analyses on these families detected two partial gene deletions, three novel mutations and five recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. On 15 individuals, across the 10 families, we performed additional whole exome or myeloid panel sequencing on blood or bone marrow to determine somatic mutations that co-exist with the germline RUNX1 mutation in tumour and pre-leukaemic states.

  Study EGAS00001004273

• FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls.

  FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls. The POP study placental biopsies were collected within 30 minutes of birth and flash frozen in RNAlater (ThermoFisher). For each biopsy, total placental RNA was extracted from approximately 5 mg of tissue using the “mirVana miRNA Isolation Kit” (Ambion) followed by DNase treatment (“DNA-free DNA Removal Kit”, Ambion). RNA quality was assessed with the Agilent Bioanalyzer and all the samples with RIN values ≥ 7.0 were used in the downstream experiments. RNA-libraries were prepared from 1g of total placental RNA with the TruSeq Stranded mRNA Library Prep Kit (Illumina) which captures polyA-tailed transcripts by oligo-dT beads, then pooled and sequenced (single-end, 50bp) using a Single End V4 cluster kit and Illumina HiSeq2500

  Dataset EGAD00001006304

• Human liver mtDNA sequencing

  BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. Clonal CCO-deficient patches of hepatocytes were identified in human liver samples, and samples were taken along a line spanning approximately from the portal triad to the central hepatic vein. Individual BAM files are named according to their patch, line and cut, where cut 1 is nearest to the portal triad, and cuts 2, 3 etc. lying further from the portal triad. Other file types include "Bulk" samples, contain sequencing data of the remaining CCO-deficient cells that were not sampled as part of the line of cuts, and "Stroma" control samples (used for identifying germ-line variants). Sequenced on NextSeq 500 platform.

  Dataset EGAD00001007991

• Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation

  Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN.

  Dataset EGAD00001005769

• Somatic mutation in edited cholangiocyte organoids

  Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.

  Dataset EGAD00001015455

• WGS dataset of Characterization of UV DNA damage in B-cell precursor acute lymphoblastic leukemia

  We characterized B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients that present with the mutational signature SBS7a. We found clear subtype specificity, but presence of SBS7a did not seem linked to heterogeneity within subtypes. To further distinguish the incidence of SBS7a in pediatric cancer we analyzed a pan-cancer WGS cohort and identified frequent SBS7a in anaplastic large cell lymphomas. As SBS7a is commonly found in skin cancers and has been linked to UV-light induced DNA damage, we compared the features of UV-light induced DNA damage in skin cancer and SBS7a in ALL, and found high similarity. We found no defects in UV damage response pathways in SBS7a-positive samples, indicating no additional UV vulnerability. Additionally, transcriptomic data showed no differences between samples with and without SBS7a. Finally we looked into the moment of exposure to the source of SBS7a by deep sequencing of diagnosis-relapse pairs and single cell whole genome sequencing of diagnosis samples with high SBS7a.

  Dataset EGAD00001015600

• WES data

  WES FASTq files of 76 bulk pre-treatment tumors and 76 matched peripheral blood mononuclear cells from GO30140 group A

  Dataset EGAD00001008129

• The polarity and specificity of antiviral T lymphocyte responses determine susceptibility to SARS-CoV-2 infection in cancer patients and healthy individuals

  We monitored patient's anti SARS-CoV-2 immune responses using an in vitro cross presentation assay. The goal of this study was to identify immune correlates of clinical protection against SARS-CoV-2 infection. Briefly, peripheral blood mononuclear cells of patient were divided into a monocyte and lymphocyte. Monocyte were differentiated into monocyte derived dendritic (mo-DC)cells using GM-CSF and Interferon alpha. Mo-DC were then loaded with SARS-CoV-2 culture lysates , or VeroE86 lysates. SARS-CoV-2 loaded mo-DC were then used to stimulates their autologous lymphocytes and T cell cytokine secretion was monitored in the supernatant. We discriminated patients producing IL-2 and patients producing IL-5. RNA sequencing was performed for 18 patients, to identify gene profile associated with IL-2 or IL-5 production.

  Dataset EGAD00001008538

• Whole exome sequencing of non-small cell lung cancer patient-derived xenografts

  Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbour actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. We generated NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Here, we completed whole exome sequencing on 122 NSCLC PDXs.

  Dataset EGAD00001008601

• Tagged-amplicon deep sequencing

  This dataset contains a collection of tumour samples from high grade serous ovarian carcinoma patients with recurrent disease collected near the point of diagnosis as well as tumour samples collected after patient relapse upon or some time after study entry. Whole blood samples were also collected from patients at study entry for the purpose of germline variant detection. The majority of diagnosis samples were preserved in neutral buffered formalin whereas the majority of post-relapse samples were preserved in universal molecular fixative (UMFIX, Sakura Finetek USA, Inc). DNA was extracted and the tagged-amplicon deep sequencing assay was applied (TAm-Seq, Forshew et al. 2002, Sci Transl Med) with the aid of fluidigm access array technology. Targeted loci were sequenced at very high depths (typically >100X) for the detection of both somatic and germline variants. Sequenced reads were aligned to the GRCh37 reference genome (release hs37d5).

  Dataset EGAD00001011058

• Genomics of acral lentiginous melanoma

  Melanoma is the most aggressive type of skin cancer, causing about 75% of dermatological cancer deaths. Acral lentiginous melanoma (ALM) is the most common subtype of melanoma in admixed Latin American populations, but very few tumour genomes and exomes, all from European-descent individuals, have been analysed across several studies. Because of this, the genomic landscape of ALM is mostly unknown. Our aim in this project is to define this landscape and identify driver somatic alterations by whole-exome sequencing a collection of ALM germline/tumour paired FFPE samples from the National Cancer Institute of Mexico. . This dataset contains all the data available for this study on 2023-03-09.

  Dataset EGAD00001010126

• The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients

  Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find novel patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a novel genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.

  Dataset EGAD00001012101

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - WGS

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015430