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• Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

  DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutational consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb) – higher than all childhood and most cancers (>7000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerases epsilon or delta. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germline bMMRD (p<10e-13). Sequential tumor biopsy analysis revealed that bMMRD/polymerase mutant cancers rapidly amass an excess of simultaneous mutations (~600 mutations/cell division), reaching but not exceeding ~20,000 exonic mutations in <6 months. Thus implying a threshold compatible with cancer cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

  Study EGAS00001001112

• Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

  IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild-type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients, mutant IDH1 and 2HG are not required for later clonal expansions.

  Study EGAS00001001854

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• WGS of T-cell and NK-cell lymphoma for ICGC (NKTL-SG)

  Lymphomas are malignancies originating from the lymphatic system and there is a worldwide significant increase in incidences of this cancer. Lymphomas can be further classified into 2 categories namely Hodgkin’s (HL), and Non-Hodgkin’s lymphoma (NHL). The latter can be divided further into B, T and NK cell NHL. Peripheral T-cell lymphoma (PTCL) and Natural Killer/ T-cell lymphoma (NKTL) arise from mature T lymphocytes and NK cells. The more common subtypes include NKTL, PTCL not-otherwise-specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL), follicular PTCL (F-PTCL), angioimmunoblastic T-cell lymphoma (AITL) and enteropathy-associated T-cell lymphoma (EATL). Whole genome analyses on T-cell and NK-cell lymphoma samples from various countries to gain a better understanding of the pathogenesis and biology of these tumors. The comprehensive profiling and comparison among patients from various countries with different etiopathogenesis will hopefully facilitate the elucidation of key pathways and underlying molecular mechanisms driving these cancers, opening up novel therapeutic strategies in the future.

  Study EGAS00001002398

• Description and determinants of the faecal resistome and microbiome of farmers and slaughterhouse workers: a metagenome-wide cross-sectional study.

  Within this study, we extracted DNA of 194 stool samples of persons living or working on pig and broiler farms (54 pig farmers, 24 broiler farmers), 70 pig slaughterhouse workers and 46 control subjects (Lifelines population living in the Northern parts of the Netherlands, and without recent antimicrobial use and occupational livestock contact). Total DNA was sequenced and metagenomic analysis was performed. Subsequently, the faecal resistomes and microbiomes were described and analysed (doi: 10.1016/j.envint.2020.105939). Highlights study: • Food chain workers are exposed to antimicrobial resistant (AMR) bacteria in livestock. • We describe faecal resistomes and microbiomes of farmers and slaughterhouse workers. • Faecal AMR gene loads in pork exposed workers exceed those in broiler farmers/controls. • Resistome and microbiome differences are shown between and within occupational groups. • On-farm working hours and working/living on a pig farm determine the faecal resistome. • Contact with livestock may be a determinant for human AMR gene carriage. This study is part of the EFFORT project: http://www.effort-against-amr.eu/.

  Study EGAS00001003944

• Genes associated with pancreas development and function maintain open chromatin in iPSCs generated from human pancreatic beta cells

  Current in-vitro islet differentiation protocols suffer from heterogeneity and low efficiency. Induced-pluripotent stem cells (iPSCs) derived from pancreatic beta-cells (BiPSCs) preferentially differentiate towards endocrine pancreas-like cells versus those from fibroblasts (FiPSCs). We interrogated genome-wide open chromatin in BiPSCs and FiPSCs via ATAC-seq, and identified ~8.3k significant, differential open chromatin sites (DOCS) between the two iPSC subtypes (FDR<0.05). DOCS where chromatin was more accessible in BiPSCs (Bi-DOCS) were significantly enriched for known regulators of endodermal development, including bivalent and weak enhancers, and FOXA2 binding sites (FDR<0.05). Bi-DOCS were associated with genes related to pancreas development and beta-cell function, including transcription factors mutated in monogenic diabetes (PDX1, NKX2-2, HNF1A; FDR<0.05). Moreover, Bi-DOCS correlated with enhanced gene expression in BiPSC-derived definitive endoderm and pancreatic progenitor cells. Bi-DOCS therefore highlight genes and pathways governing islet-lineage commitment, which can be exploited for differentiation protocol optimisation, diabetes disease modelling, and therapeutic purposes.

  Study EGAS00001002591

• Exome sequencing demonstrates a dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.

  Retinoic acid (RA) and arsenic target the PML/RARA driver of Acute Promyelocytic Leukemia (APL), their combination now curing over 95% patients. Here we report exome sequencing of 64 matched diagnosis/remission/relapses patients treated with historical RA/chemotherapy protocols. A first subgroup presents a high incidence of oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that relapses derive from pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

  Study EGAS00001002893

• An instructive role for IL7RA in the development of human B-cell precursor leukemia

  Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic cells creates a preleukemic state in transplanted NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolved to a BCP-ALL with spontaneously acquired CDKN2A deletions as commonly observed in primary human BCP-ALL. CRISPR mediated silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA resulted in robust development of BCP-ALLs in-vivo. Thus, we demonstrate for the first time that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

  Study EGAS00001005347

• A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

  Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

  Study EGAS00001005493

• Single-nuclei gene-expression analysis of pheochromocytoma and paraganglioma links tumor subtypes with tumor microenvironment

  Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumors associated with autonomic nerves. We used single nuclei-RNA-seq (snRNA-seq) for analysis of 30 PCPG representing 13 known driver genes, plus two normal adrenal medullas to dissect cell composition, refine PCPG subtypes and compare PCPG and normal tissue expression. Incorporating bulk-tissue and snRNA-seq data we identified seven PCPG gene-expression subtypes with genotype and cell type associations. The tumor microenvironment reflected HIF pathway activation and neovascularization by detection of abundant tip-like endothelial cells and pericytes concordant with VEGFA expression in neoplastic cells with mutations in VHL, genes encoding SDH subunits and MAML3-fusions. Macrophages were abundant in PCPG with distinct tumor-associated features. Schwann-cell-like cells were also enriched in some subtypes. The transcriptional profile of neoplastic PCPG cells resembled normal chromaffin cells but early chromaffin and neuroblast cell markers were expressed in some subtypes including GPR139, a putative therapeutic target for a subset of pseudohypoxic PCPG.

  Study EGAS00001005861

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• Single-cell RNA-seq of celiac disease-specific plasma cells

  Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGP) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls, and performed RNA-sequencing with clonal inference and transcriptomic analysis of 3251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGP-specific antibodies revealed a key role of a heavy-chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses. We identified transcriptional differences between CeD-specific vs non-disease-specific PCs and between short-lived vs long-lived PCs. The short-lived CD19+CD45+ phenotype dominated in untreated and short-term-treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.

  Study EGAS00001004623

• DLBCL NGS Genomic Datasets of non-China cohort from Phoenix Clinical Trial

  Study biopsies (n=773; 189 cases as China cohort and 584 cases as non-China cohort) underwent whole exome sequencing or targeted gene panel DNA sequencing and RNA sequencing, allowing the identification of somatic mutations. Tumors were assigned to DLBCL genetic subtypes as the MCD (n=110), BN2 (n=47) or N1 (n=28) using the LymphGen algorithm based on their somatically mutated genes. In younger patients (age≤60), ibrutinib plus R-CHOP was associated with a 100% event free survival (EFS) at 3-years in the MCD and N1 groups, whereas R-CHOP alone was associated with a 3-year EFS of 42.9% (p=0.01) and 50% (p=0.016) in the MCD and N1 groups, respectively. This analysis showed a benefit of ibrutinib with R-CHOP chemotherapy in particular genetic subtypes, providing mechanistic support for its survival benefit in younger patients with non-GCB DLBCL. The EGA collects RNA-Seq and NuGene targeted sequencing datasets of 584 cases for non-China cohort.

  Study EGAS00001005554

• Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

  Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We used differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR=1.63, p=5.24x10-5) and overall survival (HR=1.61, p=1.67x10-4), and validated in 177 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC=0.02), or published prognostic signatures. The signature score negatively correlated with measures of immune cell infiltration (ρ=-0.75, p<2.2x10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

  Study EGAS00001004664

• Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

  De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely-collected tissue in this setting has hindered genomic stratification and jeopardizes precision oncology efforts. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotype across 607 synchronous primary and metastatic tissue foci plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically-relevant genes, resulting in frequent discordance between select primary-restricted foci and synchronous metastases. Additional complexity was driven in several instances by polyclonal metastatic seeding from the reservoir of phylogenetically-related primary populations. When simulating standard clinical practice relying on a single tissue focus, genomic heterogeneity plus highly variable per-sample tumor fraction caused false genotyping of dominant disease. However, in silico modeling demonstrated that analysis of multiple biopsy cores can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-naive primary and metastatic lesions in de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

  Study EGAS00001006466

• Upper cortical layer-driven network impairment in schizophrenia

  Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

  Study EGAS00001006495

• scRNASeq of human innate lymphoid cells from different compartments

  Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identifiy a population of “liver-type” ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s were CD49a+CD94+CD200R1+, expressed the transcription factor T-BET, do not express the activating receptor NKp80, or the transcription factor EOMES. Similar to NK cells, liver-type ILC1s produce IFN-γ, TNF-α, and GM-CSF; however, liver-type ILC1s also produce IL-2 and lack perforin and granzyme B. Liver- type ILC1s are expanded in cirrhotic liver tissues, and they can be produced from blood-derived ILC precursors in vitro in the presence of TGF-β1 and liver sinusoidal endothelial cells. Cells with similar signature and function can also be found in tonsil and intestinal tissues. Collectively, our study identifies and classifies a population of human cross-tissue ILC1s.

  Study EGAS00001006847

• Human NXPE1 mediates variation in sialic acid O-acetylation in Colon Tissue

  Sialylation, and its modifications, have important consequences for development, differentiation and immune system regulation in nearly all human tissues. An accounting of all the genes responsible for modifying sialic acids is incomplete, with only one pathway for O-acetylation being well-defined in humans. Using whole genome sequencing of normal human colorectal tissue we identify a haplotype on chromosome 11 that is associated with differences in mild periodic acid Schiff staining (mPAS), a marker of acetylation of sialic acids. Of the genes in this region, only SNPs from NXPE1 correlate perfectly in a validation data set. NXPE1 protein expression by IHC also correlates with mPAS staining patterns in homozygous, as well as heterozygous colon crypts that have undergone spontaneous gain of the mPAS phenotype. Manipulation of NXPE1 expression with CRISPR-Cas9 causes changes to modified sialic acid levels in both 2D cell line and 3D normal colon organoid models. These findings suggest NXPE1 may cause O-acetylation of sialic acids in colorectal tissue, potentially defining NXPE as a new family of sialic acid-modifying genes.

  Study EGAS00001007704

• Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

  Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

  Study EGAS00001002606

• Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration.

  The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, termed heterocateny here, characterized by heterogeneous, interrelated, and repetative patterns of concatemerized virus and host DNA segments. Evidence of heterocateny was detected in extrachromosomal and/or intrachromosomal DNA in all cases. Unique breakpoint sequences shared across structurally heterogeneous virus-host concatemers within each cancer facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that unstable virus and virus-host concatemers in ecDNA or integrated form mediate insertion into and excision from chromosomes, capture, rearrangement, and rolling-circle amplification of host DNA, and chromosomal rearrangements. The data indicate that heterocatena is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intra-tumoral heterogeneity and clonal evolution.

  Study EGAS00001006652

• Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification (H021)

  Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

  Study EGAS00001006706

• The cellular immune and airway epithelial profile throughout childhood and in response to COVID-19 at multi-omic single cell level.

  Single-cell data gene expression data set (5’Chromium 10X) of healthy paediatric volunteers, and paediatric and adult COVID-19 patients. Gene expression was determined from samples of nasal, tracheal and bronchial brushings and blood (PBMCs). In addition to gene expression, PBMC’s were assayed by CITE-seq. A subset of samples have VDJ sequencing data for T cell receptors (TCR) and B cell receptors (BCR).

  Dataset EGAD00001007718

• Frequent mutation of the major cartilage collagen gene, COL2A1, in chondrosarcoma

  Chondrosarcoma (CHS) is a heterogeneous collection of malignant bone tumours and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1/2 in nearly half of central CHS. However, there has been little systematic genomic analysis of this tumour type and thus the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 cases of CHS. We identified hypermutability of the major cartilage collagen COL2A1 with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition we identified mutations in IDH1/2 (59%), TP53 (20%), the RB1 pathway (27%) and hedgehog signaling (22%).

  Dataset EGAD00001000358

• UK_RCC_GWAS

  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). 

  Dataset EGAD00010002310

• Very Low Tumor Mutation Burden Identifies Inflamed Recurrent Glioblastomas Responsive to Cancer Immunotherapy

  A subset of available tumors (with matched blood) from patients enrolled in a phase I clinical trial testing a recombinant poliovirus, published by Desjardins et al. NEJM 2018 (PMID:29943666), were analyzed by whole exome sequencing and RNA-seq. It was discovered that low tumor mutation burden correlated with survival outcome, and also discovered that low tumor mutation burden correlated with higher inflammatory gene signatures by RNA-seq.

  Study phs002270