The sequence of the human genome provides a foundation for understanding cellular processes in health and disease1. The organisation of this primary genetic information into cell-specific structure and function is critical to understanding the cell type-specific interpretation and execution of the genome. Epigenetic processes are essential for packaging and higher-level functional organisation of the genome, and changes therein are increasingly recognised as contributors to human disease. Building on primary data generated by multinational consortia, the International Human Epigenome Consortium2 (IHEC) has uniformly processed a collection of more than 2000 comprehensive human reference epigenomes, collectively referred to as EpiATLAS. This effort involved the development of standardised molecular and bioinformatics protocols, metadata models, and analytical tools to manage, integrate, display, and share vast amounts of epigenomic data. This includes the creation of a publicly available Epigenome Reference Registry, which provides a system for accessing protected human subject datasets and facilitates open searching of de-identified samples and experimental data. The integrated EpiATLAS ecosystem and its comprehensive human reference epigenome maps provide an unprecedented resource for the biosciences, expanding the annotated epigenomic landscape while uncovering previously unappreciated relationships among regulatory layers and revealing how epigenetic inputs underpin fundamental cellular functions and disease associations.

Table S4 includes immune signature and iCluster results.

Table S7 contains microbe screening results.

Table S1 contains cohort description, Master Patient Table and MutSigCV results.

Table S2 contains BAP1 analysis results, as well as detailed lists of YY1 and IRF8 target genes.

Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.

Supplementary materials and methods, as well as supplementary figures S1-S7.

Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.

Abstract Aim: To investigate feasibility and utility of whole genome and RNA sequencing in cancer care. The use of comprehensive personal genomic information to guide cancer treatment decisions has gained momentum in recent years. Here we present the Personalized Oncogenomics (POG) project launched at British Columbia Cancer Agency in 2012. This project uses paired tumor/normal whole genome and transcriptome sequencing to characterize a patient's tumor and inform treatment options within a clinically relevant time frame. In the past 5 years, around 600 patients with metastatic cancers (including 49 pediatric cases) have been sequenced and analyzed, representing over 50 cancer types. The breadth and depth of data in POG enable the detection of multiple types of alterations, from simple mutations, indels, and copy number changes, to more complex alterations such as gene fusion, mutation signatures, and homologous recombination deficiency score. Incorporation of gene expression data through transcriptome sequencing informs on the impact of observed genomic alterations, and provides information regarding specific diagnosis via expression comparison to other cancer subtypes. All genomic and transcriptomic variants are integrated to build a personalized tumor-specific molecular profile, identify actionable items supported by an in-house knowledgebase and publically available molecular oncology, and characterize each individual tumor by intensive pathway analysis and literature search. Such multidimensional data also impose challenges in interpretation and communication. We developed a pipeline to translate complex genomic data into clinically actionable and hypothetical recommendations for the treatment of individual patients. The pipeline produces two reports: a panel-like report that contains known SNVs and fusions with therapeutic relevance from a collection of more than 4000 events, and a second comprehensive and manually curated report to fully characterize the tumor using the whole genome and transcriptome datasets. Genomic data are presented and discussed at a multidisciplinary molecular tumor board consisting of medical oncologists, pathologists, bioinformaticians, geneticists, and biologists. This approach has enabled clinicians to make informed clinical decisions based on the genomic data integrated with other clinical features, as well as to form new treatment-related hypothesis. POG has shown that use of both whole genome and transcriptome sequencing allows identification of therapeutic targets in a significant proportion of patients. Almost 80% cases were found to have one or more actionable alterations (100% in pediatric cases), and almost one-third of these are defined only using RNA data. Based on molecular tumor board discussion, patients are directed to clinical trials, positioned to genomically informed standard-of-care options, or treated with off-label drugs. With demonstrated effectiveness, the integrative approach developed by POG not only provides molecular insight and treatment options into individual tumors, but also provides a rich resource of molecular data with matched clinical information that will aid our understanding of tumor biology and therapy response mechanisms to inform treatment strategies in the future. Citation Format: Yaoqing Shen, Martin R. Jones, Erin Pleasance, Melika Bonakdar, Carolyn Ch'ng, Caralyn Reisle, Laura Williamson, Elisa Majounie, Greg Taylor, Simon Chan, Brandon Pierce, Wei Zhang, Amir Muhammadzadeh, Eric Y. Zhao, Dustin Bleile, Karen Mungall, Nina Thiessen, Eric Chuah, Tina Wong, Richard Corbett, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Yongjun Zhao, Stephen Yip, Anna F. Lee, Rod Rassekh, Rebecca Deyell, Howard Lim, Daniel Renouf, Robyn Roscoe, Steven J.M Jones, Janessa Laskin, Marco A. Marra. Clinical application of whole genome and transcriptome sequencing in cancer care [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A184.

BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

BACKGROUNDPapillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.METHODSWe performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.RESULTSType 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).CONCLUSIONSType 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.