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• KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

  Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

  Study phs002801

• Molecular Characterization of Large Cell Neuroendocrine Carcinoma of the Lung by Multilayered Omics Analysis

  Large cell neuroendocrine carcinoma (LCNEC) is a rare lung cancer type with a very poor prognosis. The underlying molecular features remain unclear. Here, we conducted a multi-omics analysis of 27 LCNEC cases along with 7 small cell lung carcinoma and aimed to propose new classification by extracting genomic and transcriptomic features in LCNEC, leading to the elucidation of the therapeutic approaches.

  Study JGAS000832

• Asian Indian Diabetic Heart Study (AIDHS) /Sikh Diabetes Study (SDS)

  The Punjabi Sikh population is a well-defined, carefully collected homogeneous sample from northern India and the US. It has unique characteristics, which are ideal for genetic studies. Sikhs are strictly a non-smoking population and about 50% of participants are life-long vegetarians. All subjects included in the genome-wide association studies (GWAS) were recruited from one geographical location. Our population demonstrates a strong familial clustering of type 2 diabetes and related cardio-metabolic disorders that may be genetic and we believe that the contribution of alleles at specific loci are likely to be unique to Punjabi Asians compared to Europeans. Our group first showed that the association of a common variant at rs9939609 in the FTO (fat mass and obesity) gene in South Asians was independent of BMI (PMID:18598350) in contrast to Europeans where the association of same variant with T2D is mediated through obesity (PMID:17434869). These findings were later confirmed in an independent sample of South Indians (PMID:19005641), Pakistanis (PMID:21294771), and even East and South Asians in a large meta-analyses study comprising 96,551 individuals (PMID: 22109280). Earlier reported association of MTNR1B with fasting glucose concentrations and type 2 diabetes in European GWAS could not be confirmed in our Sikh cohort. On the other hand, our study revealed, for the first time, a significant protective association of another less common variant in MTNR1B with fasting glucose levels that was modulated by obesity. Ours was the first report that suggested that the low CETP activity was associated with higher CAD risk (PMID:22143414) in South Asians and that the genetic effects are significantly modulated by environmental factors (alcohol consumption). Our recent GWAS on type 2 diabetes has identified a novel locus at chromosome 13q12 in the SGCG gene (p=1.82x10-8) associated with type 2 diabetes (PMID:23300278) in Punjabi Sikhs. From these findings, we are optimistic that our resource will provide new insights to gene functions in the diabetic pathway and better help researchers to understand and translate these insights to novel therapeutic treatment and early prevention to T2D that may be important beyond Indians.

  Study phs000583

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659

• The circulating cell-free DNA landscape in sepsis is dominated by impaired liver clearance

  Circulating cell-free DNA (cfDNA) is a promising molecular biomarker. However, its utility in severe infection remains poorly understood. Here, we isolated cfDNA from sepsis patients and controls, demonstrating a 41-fold increase in the amount of cfDNA in circulation during disease. We used sequencing to reconstruct cfDNA methylomes, fragmentation profiles, and nucleosome footprints across 58 samples. We observed no difference in cfDNA composition between patients and controls, challenging the idea that cfDNA increases due to higher immune cell death during sepsis. Instead, we suggest that liver dysfunction prevents efficient clearance of cfDNA during disease. This was supported by fragmentation and end-motif patterns, both of which showed evidence of cfDNA being exposed to circulating nucleases for a prolonged period, proportionally to the extent of liver dysfunction. Variation in cfDNA of megakaryocyte-erythroid progenitor origin was also a significant contributor in sepsis, increasing over time. Moreover, we showed that cfDNA retains nucleosome footprints with cell type-specific gene activity information. We developed a novel approach to study nucleosome phasing that successfully recovers tissue-specific signatures. By combining this with single-cell data, we demonstrated that sepsis patients with liver dysfunction have higher amounts of cfDNA derived from Kupffer cells and the liver parenchyma. In conclusion, we present the first high-throughput multi-modal study of cfDNA during sepsis, which will serve as a reference point for future studies on the role of this biomarker in critical illness.

  Study EGAS50000001033

• Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

  Human cancers, including breast cancers, are comprised of clones differing in mutation content that evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment.

  Study EGAS00001000952

• Genome-Wide Association Study of Endometrial Cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2)

  Endometrial cancer, the most common gynecological malignancy in the United States, has both an environmental and genetic component. To this end, we conducted a genome-wide association study to identify genes involved in endometrial cancer using studies from the NCI-supported Epidemiology of Endometrial Cancer Consortium (E2C2). For the discovery stage we included samples from 6 cohort and 7 case control studies through 2007. The total number of cases genotyped were 2,307, white women of European descent, and 2,307 matched controls using the Illumina HumanOmniExpress platform. We conducted the replication using the Infinium HumanExome BeadChip, which successfully genotyped 177,139 variants in 1055 cases and 1778 controls from four ethnically diverse studies that are part of the Epidemiology of Endometrial Cancer Consortium (E2C2). The overall goal is to determine whether certain genotypes are predictive of future endometrial cancer risk, and whether the genotypes interact with established endometrial risk factors.

  Study phs000893

• High Altitude Pulmonary Hypertension

  The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.

  Study EGAS00001003171

• Genetic Components of Knee Osteoarthritis (GeCKO) Study: The Osteoarthritis Initiative

  The Osteoarthritis Initiative (OAI) is a publicly and privately funded prospective longitudinal cohort with a primary objective of identifying risk factors for incidence and progression of tibiofemoral knee OA. The OAI utilized a focused population-based recruitment to enroll 4,674 men and women between the ages of 45-79 years who either had radiographic symptomatic knee OA or who were without radiographic symptomatic OA in both knees but were considered high risk for OA because they had two or more known risk factors for knee OA. Subjects were recruited into the baseline phase of the OAI at multiple sites throughout the US between 2004 and 2006. All subjects were invited back for follow-up examinations to assess incidence or progression of OA annually, for up to 5 years. Phenotype data from the baseline and follow-up examinations are available for public access from the Osteoarthritis Initiative (OAI) database at http://www.oai.ucsf.edu/. The Genetic Components of Knee Osteoarthritis (GeCKO) Study was initiated in 2009 as a genetic ancillary study to perform a genome-wide association study to identify genetic variants associated with radiographic osteoarthritis. This study included 4,482 individuals participating in the parent OAI study. Following sample cleaning (e.g., removal of duplicates, sex mismatches, poor sample quality, etc.), the final sample set included 4,129 individuals.

  Study phs000955

• ALK_inhibitors_in_the_context_of_ALK_dependent_cancer_cell_lines

  Anaplastic lymphoma kinase (ALK) has recently been found to be a critical cancer gene in cases of lung cancer, neuroblastomas and lymphomas. ALK inhibitors have recently shown significant activity in lung cancer patients with tumours that harbour the EML4-ALK gene rearrangement, but already drug-resistance is emerging. We have taken a lung cancer cell line H3122 (with the EML4-ALK rearrangement) and generated clones resistant to a small molecule inhibitor of ALK by serial exposure to the drug over 8 weeks. We now wish to characterise at the exome level whether the acquisiton of resistance has been accompanied by the development of new mutations that we can take forward for further study as the potential mechansims underlying the resistance. We therefore propose to exome sequence the parental NCI-H3122 cell line as well as drug-resistant clones.

  Study EGAS00001000082