Search Results - EGA European Genome-Phenome Archive

RB1 Loss Triggers Dependence on ESRRG in Retinoblastoma

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed whole exomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. ESRRG is an essential mediator of hypoxic adaptation and cell survival in retinoblastoma, representing a promising new therapeutic target.

Study phs002859

PDAC Prognosis Biomarkers in Genomic and Transcriptomic Molecular Data

Our study was designed to identify biomarkers related to the prognosis of Pancreatic Ductal AdenoCarcinoma (PDAC) patients using genomic variants and gene expression in coding regions of the human genome (exome). PDAC is the 7th cause of cancer deaths and is among types of cancer having the poorest prognosis. To improve treatment outcomes of PDAC, biomarkers related to PDAC prognosis are needed. The goals of our study are to find genomic and transcriptomic biomarkers, which can classify prognosis subtype of PDAC patients, and eventually to predict subtypes or prognosis for each patient. In this study, we generated Whole Exome Sequencing (WES) and exome capture RNA sequencing data of 450 tumor and matched normal samples from 150 PDAC patients. Our data may be useful for understanding genomic and transcriptomic features, prognosis prediction, and precision medicine for PDAC.

Study phs002347

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

ADAGESIII: Contribution of genotype to glaucoma phenotype in African Americans

Glaucoma results in vision loss due to damage of the optic nerve that is irreversible if undetected or untreated. The most common form of glaucoma is primary open angle glaucoma (POAG). While glaucoma affects all races, persons of African descent are disproportionately affected; studies show African-Americans (AAs) are about four to five times more likely than Caucasian Americans to develop the disease. Glaucoma is the leading cause of irreversible blindness in Americans of African descent, and the second leading cause in all Americans. The lack of understanding about the etiology of POAG impedes our ability to identify and treat it early in its development. Evidence of genetic contribution in the pathogenesis of POAG is well established. Since POAG tends to run in families, it is critical to identify the genetic basis of the disease in order to develop effective therapies for early intervention. While genome wide association studies (GWAS) for glaucoma have been completed for Caucasian populations, evidence from other studies suggests that a GWAS of glaucoma specific genes to the African-American population will yield unique and important findings for both this population and for glaucoma in general. A better understanding of the relationship among the stage of disease, the rate of change, ancestry, and other important risk factors being tracked in the ongoing African Descent and Glaucoma Study (ADAGES) will allow us to evaluate the relationship between genetics, visual loss and structural damage in this high-risk cohort. The scientific plan for this new study focuses on glaucoma in ∼2058 African-Americans by detailed phenotyping of new subjects, acquisition of samples from both new and established previously phenotyped study subjects for a repository, establishment of a data coordinating center, and genome wide association studies. The recruitment, enrollment, and phenotyping of both established and new subjects occurs at five clinical centers, University of California (UCSD), New York Eye and Ear Infirmary (Mt Sinai) and Columbia University Medical Center, a private practice in the Atlanta area, the University of Alabama at Birmingham, and the Robert Cizik Eye Clinic in Houston, TX. UCSD is also the location for the Data Coordinating Center and the Repository with Robert N. Weinreb as Principal Investigator. LA BioMed at Harbor-UCLA did the genotyping with a GWAS panel of ∼1 million single nucleotide polymorphisms (SNPs) using the Illumina MEGA array under the direction of Jerome Rotter, Ida Chen, and Kent Taylor.

Study phs001673

eMERGE Network Phase III: HRC SNV and 1000 Genomes SV Imputed Array Data of 105,000 Participants

The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in June 2007 and began its third phase in September 2015. eMERGE Phase III (June 2015 - June 2020) consists of 10 study sites, two central sequencing and genotyping facilities, and a coordinating center. Included in this study are: Human Reference Consortium (HRC) single nucleotide variants and 1000 Genomes structural variants imputed array data of 105,108 eMERGE participants from nine Phase III study sites and three Phase II study site collaborators. Corresponding demographics, body mass index measurements. Case/control status for the following phenotypes: Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection. Study sites and participants include: Boston Children's Hospital: The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants'preferences;results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP. Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic health records (EHRs). EHRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): Cincinnati Children's Hospital Medical Center (CCHMC) is a pediatric institution dedicated to improving health and welfare of children and to the discovery and practical application of new genomic information to the ordinary care of children. CCHMC brings an extraordinary faculty to eMERGE III who are committed to gain a better understanding of the genesis of disease and to elucidate the mechanisms of diseases that afflict children, specifically pediatric disease phenotypes that will leverage the available eMERGE adult genomic data and electronic medical records (EMRs) to discover meaningful use results. Generation of EMR phenotype algorithms, informed by natural language processing, using heuristic and machine learning methods is ongoing. CCHMC has developed tools to evaluate adolescent return of results preferences, examined the ethical and legal obligations and potential to reanalyze results, and developed clinical decision support for phenotyping, test ordering, and returning sequencing results. The success of these eMERGE III studies is enhanced by the ongoing institutional investment made in the CCHMC Biobank, the comprehensive EMR (EPIC), the i2b2 de-identified medical record data warehouse, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. Columbia University: Columbia University Medical Center/New York Presbyterian (CUMC/NYP) Hospital system is one of the nation's largest and most comprehensive hospital systems with over 2 million inpatient and outpatient yearly visits that serves a racially and ethnically diverse urban patient population. The Columbia University GENomic Integration with EHR (GENIE) research study contributed and shared phenotype and genotype data for individuals who were recruited as part of a diverse array of initiatives within the hospital, including Northern Manhattan Study (NOMAS), Pediatric Cardiac Genomic Consortium (PCGC), Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease (AD), Alzheimer's Disease Sequencing Project (ADSP), and Genetics of Chronic Kidney Disease study. Some of these individuals had kidney or neurological problems, some were healthy adult volunteers with self-reported health status information from the medically underserved Northern Manhattan community, and others were pediatric patients with cardiac conditions. For the kidney disease cohort, patients with the diagnosis of Chronic Kidney Disease (CKD) and healthy controls were recruited to the Columbia University CKD biobank. For the NOMAS cohort, eligible participants were stroke-free, were 40 years old, and resided for at least 3 months in a Northern Manhattan household with a telephone. The PCGC study recruited parent-offspring trios with pediatric probands diagnosed with congenital heart defects (CHD). For the Caribbean Hispanics with Alzheimer's disease project, individuals from families affected by AD and with sporadic AD were recruited, along with unrelated controls. Samples for the ADSP study have been selected from well-characterized cohorts of individuals with AD diagnosis. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patients agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. Partners Health Care (Harvard): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 60,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 100 million dollars in NIH research. Kaiser Permanente Washington with the University of Washington and the Fred Hutchinson Cancer Research Center: KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~8,073.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes n=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (n=1,002), in order to allow us to enrich germline pathogenic variants. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo Vascular Disease Biorepository is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval;this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Case control study of venous thromboembolism (PI John Heit) Controls from a case control study of pancreatic cancer (PI Gloria Petersen) Mayo Clinic Biobank. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants'DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University Medical Center: BioVU, Vanderbilt's DNA databank, was designed as an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations. BioVU is currently the largest single site DNA collection world-wide, at >235,000 samples as of spring 2017.

Study phs001584

Whole-Genome and Exome Sequencing in clear-cell Renal Cell Carcinoma (ccRCC)

Study to evaluate the molecular genetics of ccRCC through integrative analyses of tumors and tumorgrafts using multiple platforms in clinically annotated samples. Genome and exome data for patients giving consent to have the information available on a public, secure, database is being submitted.

Study phs000491

Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

The Sjögren's Genetics Network (SGENE) is an international collaboration focused on identifying and understanding the genetic variations that influence Sjögren’s pathology. Collectively, SGENE collaborators from 26 different sites (5 in the United States; 21 in foreign countries) have recruited a large cohort of geographically diverse participants of European ancestry. Recruitment, sample collection, and genotyping were performed at unique SGENE sites in compliance with local institutional review board approval. High-density SNP genotyping data were collated by the Oklahoma Medical Research Foundation (OMRF) and used to perform a GWAS of Sjögren's of European ancestry. Participants underwent extensive medical assessment for Sjögren's Syndrome using internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria. Data quality control, GWAS imputation using the Haplotype Reference Consortium, panel version 1.1, and dbGaP preparation/posting were performed at the OMRF. To facilitate research focused on understanding the genetics of Sjögren's syndrome, the Genomic Summary Results from this GWAS are being made available herein using a total of n=3232 Sjögren's cases and n=17,481 controls. A total of n=8962 controls were obtained from our SGENE collaborators or from our previous study (Lessard, et al. Nature Genetics 2013. PMID: 24097067). To achieve adequate case-to-control ratios for the GWAS analyses, population-based control GWAS data were also obtained from dbGaP (phs000428.v2.p2; phs000672.v1.p1; phs000196.v3.p1; phs000187.v1.p1). In accordance with IRB approval, subject consents, and data sharing restrictions, we are also making available the individual-level genotyping data for a subset of Sjögren's cases (n=1,199) that were genotyped at the OMRF.

Study phs002723

Single Cell Analysis of Sporadic Human Basal Cell Carcinomas

To explore tumor heterogeneity in sporadic human basal cell carcinoma tumors, we profiled three individual patient tumors by scRNA-Seq and scATAC-Seq. Basal cell carcinomas (BCCs) are driven by hedgehog signaling with GLI1 representing the key downstream transcription factor that drives tumor growth. GLI1 as such is a readout of active hedgehog signaling. We identified that LY6D can mark squamous populations such as in squamous cell carcinomas (SCCs) that are negative for GIL1 and hedgehog signaling. As such, both GLI1 and LY6D can be used as biomarkers of BCCs and SCCs and their related states.

Study phs003103

Maintenance of Brain Tumor Profile on Organotypic Brain Slice Culture (OBSC)

We used uncultured tumor resection tissue from an NF2 mutation-driven grade II meningioma (MG-II) to investigate whether tumors engrafted onto organotypic brain slice cultures (OBSCs) maintained the genetic profile of the parent tumor. We prepared three groups of samples for whole exome sequencing (WES) from the same pool of dissociated MG-II tissue. Group HT is the original uncultured human tumor tissue (n = 3). Group CL is the parent tumor tissue expanded in standard in vitro cell culture until the minimum number of cells required for WES had grown. Because of initial cell loss and subsequent clonal expansion, this required six passages over the span of approximately one month (n = 3). Group BSHT is the uncultured tumor resection tissue engrafted onto OBSCs and subsequently dissected from the OBSCs at the conclusion of our standardized assay length (4 days; n = 4). WES analysis showed that tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to the parent tumor, while tumor tissue expanded in vitro displayed a distinctly different profile. Furthermore, the mutational profiles of all four BSHT biological replicates were markedly similar, indicating that each OBSC-engrafted tumor indeed contained a representative sample of the original patient tumor. A closer look at the hallmark NF2 mutations existing within all samples revealed that while all samples from the original tumor (HT1-3) and the OBSC-engrafted tumor (BSHT1-4) maintain the frame shift deletion at V24, this mutation was lost in all samples expanded in vitro (CL1-3) and replaced by mutations in other areas. Together, this data suggests that the rapid assay design and tumor-accommodating niche of our OBSC platform enables effective maintenance of the original patient tumor profile. The BBsplit algorithm from the BBtools suite was run on all samples to eliminate rat DNA contamination in the BSHT samples as well as to account for any biases that may result as a part of that process. Only the reads that were binned to the human reference were used for subsequent analysis. Reads were then mapped to the GRCh38 version of the human genome with BWA v0.7.17 and realigned together with ABRA2 v.23. Quality control was implemented using the GATK/Picard v4.1.7.0 toolkit. Somatic variants were called for each sample using the MuTect2 algorithm v4.1.7.0. Variants were merged into a single cohort variant call file and then converted to MAF via vcf2maf v1.6.21 tool. Variants were annotated using VEP v87. To identify mutations with potentially high biological impact, multiple filtering steps were applied to somatic mutation calling. First, we selected only the somatic variants that passed all filters from the MuTect2 FilterMutectCalls algorithm and second, only high/moderate impact (change coding) variants as defined by the VEP annotation were further analyzed. Over 1900 single nucleotide variants (SNVs) were detected across all samples. Figures that summarized the results were generated using maftools.

Study phs003268

Tumor Mutation Burden, Expressed Neoantigen and Immune Microenvironment in Diffuse Gliomas

A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5%of IDH-wildtype gliomas (p= 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R =−0.46, p= 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. Antigen Processing and Presentation (APP) score correlates with immune score. The APP is higher in non-hypermutator phenotype (NHMP) samples versus HMP samples in the IDH-wildtype gliomas, but higher in HMP samples versus NHMP samples in the IDH-mutant gliomas. Conclusion: TMB was inversely correlated with the immune score in the IDH-wildtype gliomas, and showed no correlation in the IDH-mutant tumors. The APP was correlated with the immune score, and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a large glioma cohort are warranted.

Study phs002653

Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer death in children, adolescents and young adults. Hodgkin and non-Hodgkin lymphoma are also important hematologic malignancies (HM) that occur in children. Each are genetic diseases with growing evidence for a germline predisposition of both familial and sporadic cases, however the inherited genetic basis of ALL/lymphoma are poorly understood. Such knowledge is essential to gain mechanistic insight into the basis of tumor formation, and to guide genetic counseling and genetic management. Here we have assembled a large collection of familial HM kindreds, and extended recurrence cohorts of ALL and HL which will be used to identify the genetic basis of familial HM, examine the frequency of germline variants in sporadic ALL and HL, and to integrate inherited and somatic genomic data. These studies have high potential to provide fundamental new insights into the inherited genetic basis of HM, to provide important information to guide clinical management, and to provide an invaluable public resource of genomic data.

Study phs001738

Neoantigen Landscape in a Hypermutated Glioblastoma Arising in a Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy

Whole genome and exome-based DNA sequencing of germline and tumor specimens from serial samples of patients with glioblastoma. The data set includes several metastases and recurrences from a patient with germline POLE-deficiency. The data reveal extensive tumor heterogeneity, clonal evolution, and genomic responses to immunotherapy.

Study phs001663

A Genome-Wide Association Study of Lung Cancer Risk

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types genotyping 515,922 single nucleotide polymorphisms (SNPs) in 5,739 incident lung cancer cases and 5,848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from 10 additional studies for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication resulting in 3,333 adenocarcinomas (AD), 2,589 squamous cell carcinomas (SQ), and 1,418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT) on chromosome 5p15.33, was associated with risk of adenocarcinoma (OR=1.23, 95%CI=1.13-1.33, P=3.02x10-7), but not other histologic types (OR=1.01, P=0.84, and OR=1.00, P=0.93, for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95%CI=1.17-1.31, P=3.74x10-14 for AD and OR=0.99, P=0.69 and OR=0.97, P=0.48, for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma. Note: The lung study dataset to be released to dbGaP and caBIG excludes 47 individuals from the PLCO cohort who consented to participate only in cancer research projects and 22 individuals because of updated QC. Thus, the released dataset is derived from 11517 subjects, 5699 cases and 5818 controls. After the updated QC, the dataset to be released to dbGaP and caBIG includes 506062 SNPs.

Study phs000336

APOLLO1: Proteogenomic Analysis of Lung Adenocarcinoma

APOLLO is a proteogenomic study seeking to describe the major genome, transcriptome, proteome and phosphoproteome alterations, subtypes, and molecular predictors of patient outcomes. This study includes 87 lung adenocarcinomas and matched normal tissues from the Lung Cancer Biospecimen Resource Network (https://lungbio.sites.virginia.edu/). Tumor tissues were profiled by whole genome sequencing, transcriptome sequencing, MS-based proteomics and phosphoproteomics, and reverse phase protein arrays. Matched normal tissues were profiled by whole genome sequencing. Clinical and sample data include survival times, patient features, and tumor characteristics.

Study phs003011

Expression of Activation Induced Cytidine Deaminase and Risk of Transformation in Follicular Lymphoma

It is currently unclear how to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression. Building on a prior study demonstrating early transformation in FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS1, and MYC, in a more contemporary cohort of 199 newly diagnosed grade 1 and grade 2 FLs using targeted capture and massively parallel sequencing. BCL2 mutations with VAF >20% occurred in 52% of cases. Among 97 FLs that did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF >20% were associated with shorter, event-free survival (EFS, median 1.4 years with these mutations versus 4.5 years without, p = 0.048), and increased risk of transformation (HR 3.01, 95% CI 1.03-8.77, p = 0.04). Other sequenced genes were less frequently mutated and did not significantly increase the prognostic value of the panel. Across the entire population, BCL2 mutations at VAF >20% were associated with decreased EFS (HR 1.58, 95% CI 1.03-2.40, p = 0.034 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.86, 95% CI 1.07-3.23, p = 0.029). Thus, high VAF BCL2 mutations remain a prognostic factor for FL even in the chemoimmunotherapy era and might need to be considered in future study design.

Study phs002845

AC-ICAM: An Atlas and Compass of Immune-CAncer-Microbiome Interactions in Colon Cancer

Fresh frozen tumor samples and matched normal colon specimens from chemotherapy naïve, consecutive patients with a histological diagnosis of colon adenocarcinoma at Leiden University Medical Center (LUMC) were subjected to multi-omics profiling at Sidra Integrated Genomics Services, part of Sidra Medicine, Doha, Qatar. This resulted in a high-quality dataset of samples collected between 2001 and 2015. Multi-step QC was performed, including assessment of the quality of the nucleic acid extraction, sequencing, and genetic concordance between DNA/RNA sequences from the same patient. After QC, this resulted in RNA sequencing on 348 tumor samples, whole exome sequencing (WES) on 281 tumor-normal sample pairs (n=562 samples), TCR sequencing of the TCR β locus (TRB) for 114 tumor and 10 matched normal samples, and 16S rDNA sequencing on 246 tumor-normal sample pairs (n=492 samples) and 42 tumor only samples, and 167 WGS non human-aligned reads of the tumor samples. Extensive clinicopathological and survival data of the cohort are available. The median follow-up time for this cohort is 4.6 years, and the distribution of gender and pathological stage are within expected ranges for this patient population with a mean age of 68. We refer to this resource as the Sidra-LUMC (SILU) colon adenocarcinoma (COAD) Atlas and Compass of Immune-Colon cancer-Microbiome interactions (AC-ICAM)."Reprinted from Nature Medicine,Roelands, J., Kuppen, P.J.K., Ahmed, E.I. et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med (2023). https://doi.org/10.1038/s41591-023-02324-5, with permission from Nature."

Study phs002978

Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.

Study phs001041

Genomic profiling for metastatic uveal melanoma from a phase I study of the protein kinase C inhibitor AEB071

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Metastatic UM patients (n=153) were treated with AEB071 in a Phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1400 mg. First-cycle dose-limiting toxicities (DLTs) were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses > 700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing (NGS) was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of PKC inhibitors with other compounds in metastatic UM.

Study phs001953

eMERGE Network Imputed GWAS for 41 Phenotypes

The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital, Children's Hospital of Philadelphia, Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University, Geisinger Clinic, Group Health Cooperative/University of Washington, Mayo Clinic, Icahn School of Medicine at Mount Sinai, Northwestern University, Vanderbilt University Medical Center) funded by the NHGRI to investigate the use of electronic medical record (EMR) systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 55,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of over forty phenotypes, including Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection, as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes. Sites and participants include: Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): Cincinnati Children's Hospital Medical Center (CCHMC) and Boston Children's Hospital (BCH) are pediatric institutions dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. The CCHMC/BCH site has been built on a five-year history of collaboration, particularly in patient electronic record (ERM)-related informatics, the basis of much of eMERGE II. CCHMC and BCH together bring an extraordinary faculty to eMERGE II who are committed to diseases that afflict children, specifically phenotypes that focus upon diseases of children in ways that will leverage the available eMERGE adult GWAS and EMRs to discover meaningful use results. CCHMC/BCH plans to demonstrate real-time execution of phenotypic selection across their two distinct pediatric institutions as a model for ensuring phenotypic standardization and for national scalability. They will also look carefully at parents' responses to results and use of their children's research results and better understand the factors that influence their decisions about learning incidental findings. In addition to patient and parent perceptions CCHMC/BCH will also explore clinician perceptions of pharmacogenetic research results after EMR integration. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patients agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. Group Health(GH)/University of Washington (UW): GH participants for the PGx project were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~6300.) Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF), or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if participants had any laboratory event of creatine kinase (CK) >1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo biobank is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval; this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University: BioVU, Vanderbilt's DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations.

Study phs000888

Transcriptional Profiling of PD-1+ and PD-1- Teff and Treg Cells in Glioblastoma and Health

PD-1 is an important immune checkpoint inhibitor that shows great promise in the clinic, particularly for melanoma and lung cancers. Since PD-1 is also expressed on infiltrating CD4+ Treg and Teffector cells in glioblastoma, we sought to better understand the role of PD-1 on these infiltrating CD4+ Treg and Teffector cells. To this end, we performed functional and transcriptional profiling using CD4+ Treg and Teffector cells isolated from healthy donors and glioblastoma patients (from both tumors and blood).

Study phs001079

Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high risk mutational patterns

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by poor overall survival despite advances in anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing in 23 patients with newly diagnosed pPCL. The results reveal an enrichment of complex structural changes and high risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular pPCL patients with traditional low risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group.

Study phs002022

Genomic Profiling of Sequentially Acquired Metastatic Sites from an "Exceptional Responder" Lung Adenocarcinoma Patient Reveals Extensive Genomic Heterogeneity and Novel Somatic Variants

We employed next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his seven year course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ~1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies demonstrated increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy due to L869R mutation and increased migration due to ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a sub-clone metastasized early from the primary site and evolved independently in lymph nodes.

Study phs001159

Neuroblastoma Genome-Wide Association Study (NBL-GWAS)

Neuroblastoma is a malignancy of the developing sympathetic nervous system that most commonly affects young children and is often lethal. The etiology of this embryonal cancer is not known. We have performed a whole genome scan for association of neuroblastoma with SNP genotypes and copy number variation to discover predisposition loci. We therefore initiated a genome-wide association study (GWAS) in 2007 focused on neuroblastoma patients identified through the Children's Oncology Group (COG; 238 member institutions). Control patients for this study are children cared for at the Children's Hospital of Philadelphia (CHOP) without a diagnosis of cancer. The study was designed to collect up to 5000 neuroblastoma cases and 10,000 controls and is powered to detect common susceptibility variants in Caucasian and African American patients. Whole genome genotyping is being performed on the Illumina HH550 SNP array.

Study phs000124

CIDR: Discovery, Biology, and Risk of Inherited Variants in Glioma

This is a gliogene brain tumor family study. This study includes glioma cases with a family history of glioma in a first, second, or third degree relative. 

Study phs002250

Lineage Plasticity and Immune Cell Heterogeneity Are Coordinately Dysregulated Through Changes in FOXA1 Expression in Bladder Cancers with Squamous Differentiation

We performed whole exome sequencing (WES) of paired, macrodissected regions of urothelial carcinoma (UC), not otherwise specified (NOS-UC) and squamous differentiation (SqD) from 21 bladder tumors in which distinct and separable NOS-UC and SqD regions were present (total 42 exomes, in addition to matched normal exomes). Mean tumor mutational burden (TMB) was higher in the SqD versus the NOS-UC regions. Consistent with the higher TMB, the SqD regions also had a higher neoantigen burden than the patient-matched NOS-UC regions. The SqD regions also exhibited higher karyotypic complexity with a higher median ploidy relative to the paired NOS-UC regions. Phylogenetic analysis of the WES data confirmed that the morphologically distinct regions of all 21 tumors arose from a shared precursor with a median of 68 (range 16 – 852) non-synonymous mutations shared between the NOS-UC and SqD regions, and the overall data were indicative of early branched evolution. As whole exome sequencing did not identify a shared mutational alteration or genomic signature unique to the SqD or NOS-UC components, we therefore performed expression profiling of separable SqD and NOS-UC regions of 12 bladder tumors from the WES cohort with RNA quality sufficient for whole transcriptome RNA-sequencing (RNAseq, total of 24 regions). Based on centroid clustering analysis of expression data, all 12 regions of SqD were basal-squamous subtype based on the TCGA molecular classification schema. Notably, 8 of the NOS-UC regions were also basal-squamous subtype, with only four pairs exhibiting discordant transcriptional subtypes (three NOS-UC regions were luminal-infiltrated, one luminal-papillary). To better quantify differences in the transcriptional profiles of the paired NOS-UC and SqD regions, we used single sample gene set enrichment analysis (ssGSEA) to assess for enrichment of luminal or basal-squamous gene expression. ssGSEA analysis revealed that the SqD regions expressed higher levels of basal-squamous genes based on the BASE47 gene set and UPK/KRT gene sets; whereas the matched NOS-UC regions expressed higher levels of luminal genes. These differences in the levels of expression of basal and luminal genes were observed even in cases in which both the NOS-UC and SqD regions were basal-squamous subtype based the TCGA molecular classification schema. Exomes from eight patients in this study have previously been deposited in dbGaP: accession number phs001783 as part of the study "Exome Recapture and Sequencing of Prospectively Characterized Clinical Specimens From Cancer Patients".

Study phs002357

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