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• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000229

• Defined Lifestyle and Germline Factors Predispose Asian Populations to Gastric Cancer

  Gastric cancer (GC) is one of the leading causes of cancer mortality throughout the world, with the highest incidence in east-Asia. Although the somatic genetics of GC has extensively been characterized by recent advances in cancer genome sequencing, the germline and environmental effects on GC and their ethnic differences have poorly been understood. Here, we performed genomic scale trans-ethnic analysis of 531 GC cases (319 Asian and 212 non-Asians), by integrating east-Asian and public GC datasets. There is one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, and almost all the cases in the subclass are attributable to alcohol intake behavior, smoking habit, and Asian-specific ALDH2 defective allele. Alcohol-related GCs have low mutation burden and a characteristic immune profile of increased B-cell infiltration into the tumor area in relation to cancer cell-intrinsic CXCL13 chemokine expression. In addition to germline variants of genes involved in BRCA pathways, we found frequent (7.4%) germline CDH1 variants among Japanese GCs. Most of them were attributed to a few recurrent SNVs shared by both Japanese and Koreans, suggesting the existence of common ancestral events and widespread distributions of these pathogenic variants among east-Asian populations. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective-ALDH2 allele or to germline CDH1 variants. These results revealed uncharacterized impacts of germline variants and their interplays with lifestyles in the high incidence areas.

  Study JGAS000228

• Whole Exome Sequencing data of six chRCC tumors corresponding to three patients

  Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients’ primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients’ sensitivity to mTOR inhibition. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

  Study EGAS00001007104

• Whole Exome and Transcriptome Sequencing in Sporadic ALS

  Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons. Although many efforts have been done to elucidate molecular factors involved in the onset and progression of the disorder, the causes of ALS are yet unknown and undefined. Transcriptome studies, based mostly on microarrays, have revealed multiple perturbations of the motor neuron function, supporting the current idea that several cellular events contribute to the pathobiology of the disease, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, abnormal calcium metabolism and altered axonal transport. In the present study, we have deeply sequenced the whole transcriptome of ventral horns of the human lumbar spinal cord from matched control and ALS post-mortem donors. Whole exome sequencing from the same donors has also been performed to exclude known genetic variants associated to the familiar form of ALS. In addition, to characterize the ALS transcriptome we have sequenced the RNA fraction at low molecular weight in the same tissues and individuals. Genomic and transcriptomic reads have been generated using the Illumina HiSeq2000 sequencer.

  Study phs000747

• E5103 Correlative Studies

  ECOG-ACRIN E5103 (E5103) was a phase III adjuvant breast cancer trial that randomized 4994 patients with node-positive or high-risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks (at the discretion of treating physician), for four cycles of adriamycin and cyclophosphamide (AC) followed by 12 weeks of weekly paclitaxel (80 mg/m2) alone (Arm A), or to the same chemotherapy with either concurrent bevacizumab (Arm B), or concurrent plus sequential bevacizumab (Arm C). To develop predictive genetic biomarkers for chemotherapy efficacy and toxicities, we have successfully performed genome-wide genotyping and whole exome sequencing in the germline (blood) DNA of 3215 and 672 patients, respectively, from the E5103 trial to investigate the association of genetic variants with chemotherapy efficacy and toxicities. Case and control studies were performed with genome-wide analyses (GWAS) and whole exome analyses (WES) across all arms of E5103 to identify genotypes at single-nucleotide polymorphisms (SNPs) and deleterious gene mutations that were associated with paclitaxel-induced peripheral neuropathy (TIPN). Through GWAS, we have identified a SNP, rs3125923, and through WES, Cytochrome P450 oxidoreductase (POR), that was significantly associated with grade 3-4 TIPN.

  Study phs003201

• eMERGE Phase III Clinical Center at Partners HealthCare

  The Partners HealthCare Biobank is a large research data and sample repository working within the framework of Partners Personalized Medicine. It provides researchers access to high quality, consented samples to help foster research, advance understanding of the causes of common diseases, and advance the practice of medicine. The Partners Biobank provides banked samples (plasma, serum and DNA) collected from consented patients. These samples are available for distribution to Partners HealthCare investigators with appropriate approval from the Partners Institutional Review board (IRB). They are linked to clinical data that originates in the Electronic Medical Record (EMR), as well as additional health information collected in a self-reported survey. The Partners Biobank will be genotyping 25,000 subjects with the Illumina Multiethnic Beadchip 1.6 million SNPs with exome and custom content (> 60,000 LoFs). Of the participants genotyped so far, 4929 of 4962 (99.3%) individuals have genotype data that passed the default quality thresholds for the Infinium array (call rate >= 0.99). We are submitting the genotype data to dbGaP for 4929 subjects with 12 phenotypes (based on icd9 codes). We will do annual releases until we reach the full 25,000 genotyped subjects.

  Study phs000944

• Epigenetic Biomarkers of Aging

  The aim of the study was to discover new epigenetic biomarkers of aging. We used a genome-wide screen for genetic loci showing consistent changes of DNA methylation with progressive aging. Blood DNA samples from 19 apparently healthy individuals aged 22-80 years obtained from the NINDS repositories were analyzed for DNA methylation using Reduced Representation Bisulfite Sequencing. We followed the New England Biolabs (NEB) protocol for methylated adaptors as described previously. Briefly, 1 microgram of genomic DNA was spiked with 100 picograms of lambda phage DNA as the unmethylated standard and digested with MspI endonuclease at C’CGG sites. Ends of restriction fragments were filled in, 3’-dA tailed and methylated adaptors were ligated to the ends of restriction fragments. Bisulfite treatment using the Epitect kit (Qiagen) followed. Bisulfite-converted libraries were amplified using EpiMark Taq DNA polymerase (NEB) and primers with dual barcode indices. The libraries were pooled and sequenced on Illumina HiSeqX instrument using paired end reads of 150 bases. We used Bismark v0.23.1 to align the sequences to hg19 human genome assembly. We used methylKit v1.22.0 to analyze differential methylation in individuals of different ages.

  Study phs003046

• Pharmacogenomic Interactions in Glioblastoma Cell Line Models

  Glioblastoma (GBM) is a lethal disease without effective treatments. To advance toward effective therapeutic approaches that are biomarker-driven, there is a need for new targeted agents and to develop accurate preclinical models that encompass its cellular and molecular diversity. Historical cell line models poorly represent molecular diversity of GBMs, so we developed a living tissue bank encompassing 103 patient-derived GBM cell lines (PDGCLs) as a platform for preclinical pharmacogenomic investigation at scale. Thirty-four PDGCLs were submitted to a comprehensive molecular characterization of copy number alterations and mutations using whole exome sequencing (WES) and gene expression (microarrays), and tested against a panel of 390 small molecules at sixteen different duplicated concentrations. After integrating and systematically correlating molecular alterations with drug sensitivities, we yielded 8,083,140 pharmacogenomic interactions, and discovered novel drug and biomarker combinations which help to prioritize highly effective novel candidate treatments in GBM. Our findings demonstrate the utility of deep characterization of large numbers of models from a single disease to detect complex predictors of compound sensitivity, and indicate novel therapeutic approaches for a large fraction of patients with GBM.

  Study phs001793

• Single Duplex DNA Sequencing with CODEC Detects Mutations with High Sensitivity

  Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules (single duplexes) to discern the true mutations on both strands. Here, we present Concatenating Original Duplex for Error Correction (CODEC) which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than Duplex Sequencing. CODEC revealed mutation frequencies of 2.72 x 10-8 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability (MSI) with 10-fold greater sensitivity, and mutational signatures and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations which are commonly obscured by NGS errors. We applied CODEC to clinical colon and breast neoplasm samples and uncovered expected mutational signatures including homologous recombination deficiency (HRD) and MSI.

  Study phs003255

• Genomic Landscape of Colorectal Cancer in a Multi-Ancestry Cohort

  Elucidating the tumor mutational landscape of colorectal cancer (CRC) in admixed and ancestrally diverse populations is essential to enable precision medicine advancements that benefit individuals of all backgrounds. This study draws from the Latino Colorectal Cancer Consortium (LC3) and other prior initiatives to characterize and examine the somatic mutational patterns of colorectal tumors in Hispanic/Latino/Latina patients (henceforth referred to as Latino) as compared to other racial and ethnic populations. It includes paired tumor-normal whole-exome sequencing from 718 patients with primary CRC (128 Latino and 469 non-Latino individuals) to investigate the associations between somatic mutational features and both self-reported ethnicity and genetic ancestry. Somatic mutations and inherited variants were called, and global genetic ancestry proportions (African, Asian, European, Native American) were estimated from inherited variants using ADMIXTURE based on reference samples from the 1000 Genomes Project (1KGP) and the Population Architecture using Genomics and Epidemiology (PAGE) Study. Associations between genetic ancestry and gene-level mutational status, microsatellite instability status, and tumor mutational burden were estimated using logistic regression, after adjusting for age at diagnosis, sex, tumor location, and stage.

  Study phs003464