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• Association of Age at Diagnosis and Genetic Mutations in Patients with Neuroblastoma

  Neuroblastoma is diagnosed over a wide age range from birth through young adulthood, and older age at diagnosis is associated with a decline in survivability. We performed whole genome sequencing of DNA from diagnostic tumors and their matched germlines from 40 patients with metastatic neuroblastoma obtained between 1987 and 2009. To identify genetic lesions that are associated with age at diagnosis in patients with metastatic neuroblastoma. Age groups at diagnosis included infants (0-18 months), children (18 months-12 years), and adolescents and young adults (>12 years). To confirm the findings from this discovery cohort, validation testing using tumors from an additional 64 patients obtained between 1985 and 2009 was also performed. Formalin-fixed paraffin-embedded tumor tissue was used for immunohistochemistry and fluorescent in situ hybridization. Telomere lengths were analyzed using the whole genome sequencing data, quantitative polymerase chain reaction and fluorescent in situ hybridization

  Study EGAS00001000213

• Targeted sequencing of head and neck squamous cell carcinomas

  Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

  Study EGAS00001002979

• Genome Landscape of High-Grade Serous Ovarian Cancer

  Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

  Study EGAS00001000397

• High number of somatic mutations found in the healthy blood compartment of a 115-year-old woman reveals oligoclonal hematopoiesis

  The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole genome sequencing, we estimate that ~450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment of a 115-year old woman. The detected mutations appear to have been harmless passenger mutations: they were enriched in non-coding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes.The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  Study EGAS00001000660

• Integrated genetic and epigenetic analysis defines novel molecular clusters in rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. To unravel the genetic/epigenetic basis of RMS, we studied 60 RMS cases using whole exome/transcriptome sequencing, copy number (CN) profiling, and DNA methylome analysis. Based on DNA methylation patterns, RMS was clustered into 4 distinct subtypes, which exhibited remarkable correlation with mutation/CN profiles, histological phenotypes, and clinical behaviors. A1 and A2 subtypes, especially A1, largely corresponded to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes were characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite generally poor prognosis in RMS, patients in E1 cluster exceptionally showed excellent prognosis. Our results highlight the close relationship between DNA methylation status and gene mutations and biological behavior in RMS.

  Study EGAS00001000884

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma - RNA-seq

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004552

• Chromosomal copy number heterogeneity predicts survival rates across cancers

  Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis1,2. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing3. Here, we introduce a scalable measure of chromosomal copy number heterogeneity that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 35 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

  Study EGAS00001004702

• A comprehensive assessment of somatic mutation detection in cancer using whole genome sequencing

  As whole genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Using tumor-normal sample pairs from two different types of cancer, chronic lymphocytic leukemia and medulloblastoma, we conducted a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines, and even validation methods. Here we show that using PCR-free methods and increasing sequencing depth to ~100x showed benefits, as long as the tumor:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artifact-prone nature of the raw data and lack of standards for dealing with the artifacts. However, armed with the benchmark mutation set we have created, we show that many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

  Study EGAS00001001539

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004551

• Integrated genomic characterization of IDH1 mutant Glioma malignant progression

  Gliomas represent approximately 30% of all central nervous system tumors, and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade Isocitrate Dehydrogenase 1 (IDH1) mutant gliomas, we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing, copy number, gene expression and DNA methylation profiling, demonstrated non-linear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways, up-regulation of the FOXM1- and E2F2-mediated cell cycle transition genes, as well as epigenetic silencing of developmental transcriptional factors bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extra-terminal (BET) family as a potential therapeutic approach.

  Study EGAS00001001588