Search Results - EGA European Genome-Phenome Archive

Single-Cell Genome Sequencing of Gastrointestinal Carcinomas

We experimentally derived copy number profiles and transcriptome profiles of gastrointestinal cancers using single cell sequencing. Using a microfluidic droplet partitioning system, we isolated individual cells of a suspension from a primary solid tumor into droplets. These droplets tag the resultant genomic or transcriptomic material with an identifying barcode that enables bioinformatic single cell tracking. From this joint analysis, we determined the overall level of genomic instability for gastrointestinal cancers as well as transcriptomic consequences from these events.

Study phs001711

Ghana Prostate Study

Participants were recruited through the Ghana Prostate Study-a population-based component, and a clinical component. The population-based component was a probability sample designed using the 2000 Ghana Population and Housing Census data in an attempt to recruit approximately 1,000 men aged 50-74 years in the Greater Accra region (~3 million people), which successfully recruited 1,037 healthy men between 2004 and 2006 with a response percentage of 98.8 %. Consented individuals underwent an in-person interview, and within 7 days had a digital rectal examination (DRE) and provided an overnight fasting blood sample for prostate-specific antigen (PSA) testing, biomarker assays, and genetic analysis. Subjects who had a positive screen by PSA (>2.5 ng/ml) or DRE underwent a transrectal ultrasound-guided biopsy. A total of 73 histologically confirmed prostate cancer cases were identified through the population-based screening component of the Ghana Prostate Study and were included in the case population in the published GWAS (Cook et al., Human genetics, 2013). From the remaining 964 screen-negative individuals, 836 had at least 20 μg DNA extracted and available for analysis, and 500 of these were matched to cases for analysis by age (in 5-year categories). In the Ghana Prostate Study, we recruited 676 prostate cancer cases at Korle Bu Teaching Hospital in Accra, Ghana, between 2008 and 2012. All consented cases were interviewed and provided an overnight fasting blood sample. At the time of selection for this analysis we had recruited 582 prostate cancer cases, from which we selected 427 for analysis. Combined with the 73 cases diagnosed through the population-based component of the study, this yielded 500 available prostate cancer cases for analysis.

Study phs000838

Characterization of Immune-Related Gene Expression in Lung Cancer

We performed a comprehensive analysis of inter- and intratumor heterogeneity of immune gene expression in 160 lung cancer patients from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. The transcriptome was profiled with RNA sequencing in 269 tumor samples and 110 normal tissue samples from 160 subjects.

Study phs002346

Gabriella Miller Kids First Pediatric Research Program for Infantile Hemangiomas Associated with Multi-Organ Structural Birth Defects

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. Infantile hemangiomas are the most common benign vascular tumor in infants, affecting 4-5% of children. Thirty percent of segmental infantile hemangiomas on the face and scalp are associated with birth defects of multiple organs. This condition is known as PHACE, an acronym for posterior fossa brain malformations, segmental facial hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and sternal clefting. Genomic analysis of PHACE will inform treatment and expand knowledge about the causes of birth defects affecting the brain, arteries, heart, eye, midline development and hearing. The knowledge gained in this study will be used to drive strategies for prevention and provide critical targets for treatments for a range of birth defects and infantile hemangiomas.

Study phs001785

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

Molecular Epidemiology of Colorectal Cancer (MECC) Metastasis Study: A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis

This study compared Ashkenazi Jewish individuals with Stage IV metastatic colon cancer to those with non-metastatic Stage I or II colon cancers. A genome-wide association study, using a 2-stage design, identified a significant association with rs60745952.

Study phs001045

Whole Exome Sequencing of DNA from Pre-and Post-Chemotherapy Needle Biopsies of Triple Negative and Inflammatory Breast Cancers Enrolled in the S0800 Trial

Purpose: The purpose of this study was to assess the somatic mutation landscape of breast tumors before and after neoadjuvant chemotherapy. The data includes whole exome sequencing of pre- and post- tissues that were collected in the context of an already published clinical trial SWOG S0800 (ZA Nahleh et al. Breast Cancer Research and Treatment. 158:485-495, 2016). The trial compared the efficacy of sequential nab-paclitaxel followed or preceded by doxorubicin/cyclophosphamide anthracycline chemotherapy with or without bevacizumab as preoperative therapy for stage II-III breast cancer. Experimental Design: 29 pre-treatment biopsies and 9 matching post-treatment surgically resected cancer tissues were available for analysis and were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. The 9 paired samples with residual invasive cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. No matching normal tissues were available for germline sequencing and therefore we used n=7 post-treatment breast tissues without residual cancer (i.e. complete eradication of cancer by therapy) as a normal cohort to facilitate somatic variant calling.Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes are affected in different patients.

Study phs001883

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

Development and Use of Network Infrastructure for High-Throughput GWA Studies

The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer's Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt's BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer's disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer's Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer's disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has ≥ 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70°C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under §46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt's broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

Study phs000234

University of Texas PDX Development and Trial Center Grant

The goal for the University Texas PDX Development and Trial Center (UTPDTC) is to optimize personalized biomarker-based cancer therapy and identify effective targeted drugs based on the molecular characteristics of each tumor. Our short-term goals are to establish a biobank of clinically, and molecularly-annotated Patient-Derived Xenografts (PDXs) and to use PDXs as a platform for preclinical drug development and biomarker discovery. The primary goal for UTPDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations. These models will allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly defined subsets of tumors. The goal of the Patient-Derived Xenograft Core is to provide high-quality clinically relevant and molecularly annotated PDX models for the research projects proposed in the University of Texas PDX Development and Trial Center (UTPDTC) grant application and to the research activity of the NCI PDX Development and Trial Centers Research Network (PDXNet) by leveraging PDX resources at our institutions and developing new PDX models from human cancer specimens using rigorous quality standards so that the models can be used to guide clinical trial development. The PDX models developed and/or characterized by the PDX Core will be available to other cancer researchers through the PDXNet and NCI Patient-Derived Models Repository (PDMR).

Study phs001980

High-Resolution Clonal Mapping of Multi-Organ Metastasis, and Resistance to Neoadjuvant Chemotherapy, in Triple Negative Breast Cancer

Clonal dynamics during metastasis were studied in two patient-derived xenograft (PDX) models established from treatment-naive primary breast tumors from TNBC patients diagnosed with concurrent metastatic disease. Genomic sequencing and barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and metastases. Polyclonal seeding and maintenance of low-abundance subclones was observed in each metastatic lesion examined. Lung, liver, and brain metastases were enriched for an identical population of subclones. Clones dominating multi-organ metastases shared a genomic lineage. Thus, properties of rare mammary tumor subclones enabled the seeding and colonization of metastases in multiple secondary organ sites. In this study, patient-derived xenograft (PDX) models of treatment-naive TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after chemotherapy maintained the subclonal architecture of untreated tumors yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to chemotherapy-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Taken together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as a chemotherapy resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes as well as maintenance of stable subclonal architecture, demonstrating that PDXs capture molecular features characteristic of human TNBC chemoresistance.

Study phs001742

Extent and Significance of Bacterial DNA Integrations in the Human Cancer Genome

The integration of exogenous DNA into the human genome can cause somatic mutations associated with oncogenesis. For example, the insertion of HPV DNA into human chromosomes is the single most important event leading to tumorigenesis in cervical cancer. It is also now preventable with vaccines against HPV. In contrast to viral DNA integrations, the instances and repercussions of bacterial DNA integration into the somatic human genome are less clear. Yet bacterial DNA integrations (BDI) found to be associated with tumorigenesis could also be prevented using therapeutics like vaccines that limit exposure to the bacteria. Previous analysis of publicly available sequencing data from the Cancer Genome Atlas (TCGA) showed BDIs from Pseudomonas spp. rRNA into the 5'-UTR of four proto-oncogenes as well as in Ig (the immunoglobulin gene) of gastric cancer samples. The original samples from TCGA were not available to validate these findings. Therefore, a different cohort of gastric cancer patients was identified in order to establish the presence BDIs. Whole exome sequencing was completed on seven tumor samples and six adjacent gastric samples, as well as one intestinal metaplasia sample and one non-atrophic gastritis sample. Four of those samples were also investigated with transcriptomics and whole genome sequencing. Given that 15-20% of cancers worldwide are linked to infections, more work is needed to understand the role of infectious agents in oncogenesis and the mechanisms underlying that role.

Study phs001936

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

Integrated Genomic and Transcriptomic Analysis of Small Cell Lung Cancer Reveals Inter- and Intratumoral Heterogeneity and a Novel Chemotherapy-Refractory Subtype

We integrated histology, transcriptome, exome, and treatment outcomes of small cell neuroendocrine cancer (SCNC) from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of neuroendocrine (NE) differentiation and transcriptomic subtypes (ASCL1, NEUROD1, POU2F3, YAP1 and ATOH1). High NE SCNCs were more likely to benefit from replication stress-targeted therapies, in contrast to non-NE tumors which were more likely to respond to immune response-targeted therapies.

Study phs002541

International Standards for Cytogenomic Arrays

The International Standards for Cytogenomic Arrays (ISCA) Consortium is a rapidly growing group of clinical cytogenetics and molecular genetics laboratories committed to improving quality of patient care related to clinical genetic testing using new molecular cytogenetic technologies including array comparative genomic hybridization (aCGH) and quantitative SNP analysis by microarrays or bead chip technology. The ISCA Consortium is now working with the sequencing community to extend the goals of standardization, collaboration, and data sharing. To reflect this combined effort, we are becoming ICCG, or the International Collaboration for Clinical Genomics. Efforts of the Consortium include: Clinical Utility: The ISCA Consortium has made recommendations regarding the appropriate clinical indications for cytogenetic array testing (Miller et al. AJHG 2010, PMID: 20466091). Currently, discussions are focused on pediatric applications for children with unexplained developmental delay, intellectual disability, autism and other developmental disabilities. A separate committee has been developed to address appropriate cancer genetic applications (http://www.urmc.rochester.edu/ccmc/). Evidence-based standards for cytogenomic array design: The Consortium will develop recommendations for standards for the design, resolution and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics (cytogenetics and molecular genetics), genomics and bioinformatics. This design is intended to be platform and vendor-neutral (common denominator is genome sequence coordinates), and is a dynamic process with input from the broader genetics community and evidence-based review by the expert panel (a Steering Committee with international representation). Public Database for clinical and research community: It is essential that a publicly available database be created and maintained for cytogenetic array data generated in clinical testing laboratories. This will be integrated into the current dbGaP database at NCBI/NIH and released through dbVar, and curated by a committee of clinical genetics laboratory experts. The very high quality of copy number data (i.e., deletions and duplications) coming from clinical laboratories combined with expert curation will produce an invaluable resource to the clinical and research communities. Standards for interpretation of cytogenetic array results: Using the ISCA Database, along with other genomic and genetics databases, the Consortium will develop recommendations for the interpretation and reporting of pathogenic vs. benign copy number changes as well as imbalances of uncertain clinical significance. Membership in the ISCA Consortium is open to all individuals and laboratories involved in cytogenetic array testing who are committed to free data sharing and to participation in a process to develop evidence-based standards and guidelines to improve patient care. ISCA is available through dbVar: http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd37/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd75/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd45/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd101/

Study phs000205

Small Intestine Neuroendocrine Tumors (Carcinoid Tumors)

The diagnosed incidence of small bowel neuroendocrine tumors (NETs) is increasing. While patients with localized disease can be treated surgically, those with metastatic disease currently have few treatment options. The success of biologically targeted therapies in other malignancies has led to interest in the molecular alterations underlying the pathogenesis of these NETs. To identify genetic aberrations in small intestine NETs, we generated copy number profiles from 31 primary and metastatic tumors and performed whole-exome sequencing on a subset of 29 primary small intestine NETs and 24 metastatic NETs in parallel with normal blood DNA. Whole-genome sequencing data was generated on 15 tumor/normal pairs and 5 primary/metastasis/normal trios. The global genetic landscape of small bowel NETs is relatively quiet. Consistent with previous studies, the overwhelming majority of tumors were characterized by loss of chromosome 18 and, to a lesser extent, other chromosome arm gains and losses. In stark contrast to arm-level alterations, recurrent high-level focal amplifications and deletions were much less prevalent in these tumors. High-throughput mutation screening and exome sequencing revealed similarly low rates of somatic mutation in NETs (median of 0.77 non-silent mutations per megabase (Mb) of coding DNA) compared to other recent cancer exome sequencing efforts. Our analysis of this cohort identified only a single, statistically significant recurrent somatic mutation targeting the cyclin-dependent kinase inhibitor gene, CDKN1B, encoding p27.

Study phs000579

Functionally Active Copy Number Variants Associated with Prostate Cancer Risk

Prostate cancer is a leading cause of cancer death in males throughout the world and has the largest estimated effect of heritability among the most common tumor types. Copy Number Variants (CNVs) are a recently recognized class of human germline polymorphisms (Iafrate AJ, et al. (2004) Nat Genet 36, 949-951; Sebat J, et al. (2004) Science 305, 525-528.) and are associated with a variety of human diseases, including cancer. This study characterized 1,903 individuals from the Tyrol Early Prostate Cancer Detection Program (Bartsch G, et al. (2008) BJU Int 101, 809-816) using a computational framework (Banerjee S, et al. (2011) PLoS One 29;6(3)). The study results establish non-coding and coding germline CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression. The study "Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk," Demichelis F, Setlur SR, Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6686-91.

Study phs000487

Sequence Analysis of Mutations and Translocations Across Breast Cancer Subtypes

This study combined whole exome (103 samples) and whole genome (22 samples) sequencing over a total of 108 breast tumors and matched normal DNA to identify novel mutations and translocations. Samples were subjected to paired-end Illumina sequencing with goal of 30x coverage of tumor/normal for whole genomes and 100x tumor/normal coverage for whole exomes. From these sequences, we used various computational techniques to identify somatic point mutations, insertion/deletions and structural rearrangements in these tumors. From these data, we identified new insights into the rates of background mutations in these cancers, novel recurrent mutated genes, and multiple gene rearrangements. One of these rearrangements appears to be a recurrent event in breast cancer.

Study phs000369

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

Genetic Epidemiology of Ovarian Cancer Histotypes

Epithelial ovarian cancer is a highly fatal malignancy with known genetic etiology; however, it is estimated that a substantial portion of narrow sense heritability remains to be discovered. The goal of this research was to use genetic information from distantly related ovarian cancer cases to identify regions of the genome that may harbor rare risk variants for epithelial ovarian cancer. The study was conducted in the setting of the Utah Population Database, a statewide data resource in which extensive ancestry data are linked to Utah Cancer Registry records. Focusing on families with a statistically significant excess risk of epithelial ovarian cancer, we used the Infinium Global Screening Array v.3.0 to generate germline genotyping data for distantly related cases. We then applied Shared Genomic Segment Analysis to each set of related cases to identify genomic regions that may harbor ovarian cancer risk variants. Eleven regions were identified. Genotype data are available through dbGaP for one case from each pedigree. Genotype data from other ovarian cancer cases within the high-risk pedigrees as well as the pedigrees' corresponding structures can be requested and made available with approval from the Utah Resource for Genetic and Epidemiologic Research (RGE).

Study phs003140

National Cancer Institute (NCI) Prostate Cancer Genome-Wide Association Study for Uncommon Susceptibility Loci (PEGASUS)

This genome-wide association study was funded by the National Cancer Institute (NCI) to identify uncommon susceptibility loci for prostate cancer. A total of 4,600 prostate cancer cases and 2,840 controls of European ancestry from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were genotyped using the Illumina HumanOmni2.5 and passed rigorous quality control filters. Additional genotype data (available in dbGap under other accession numbers) from 101 independent controls of European ancestry scanned with the HumanOmni2.5 were also included, resulting in a total of 4,600 cases and 2,941 controls for the published analysis. SNPs from the most promising regions, as determined by rank p-value, under multiple different models as well as select candidate genes were taken forward for replication using a custom Iselect chip in 6,575 cases and 6,392 controls of European ancestry. Results from the primary scan after imputation were then meta-analyzed with the Iselect results as well as results from previous GWAS. In a combined meta-analysis of the primary scan together with the custom Iselect replication and a previous GWAS, thirteen loci reached genome-wide significance (P < 5 x 10-8) for prostate cancer overall; however, each of them confirmed a previously reported locus. Although they did not reach genome-wide significance, we found evidence for two new suggestive loci at chromosome 16q22.2 (PKD1L3, rs12597458, P = 9.67 x 10-8) and 6p22.3 (CDKAL1, rs12198220, P = 2.13 x 10-7). In a combined case-only analysis of 12,518 prostate cancer cases, we identified two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49x10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18x10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85x10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). Only the cases and controls genotyped on the HumanOmni2.5 specifically for this study are included under this accession number. Controls (n=101) genotyped with the HumanOmni2.5 for another study are posted under a different accession number. Please note that the majority of prostate cancer cases and controls genotyped in CGEMS (and posted under a different accession number) are included in this study.

Study phs000882

Hi-C Profiling of Solid Tumor Samples

Structural variants, such as translocations, inversions, duplications, and deletions, have long been recognized as mutations that can contribute to the initiation and progression of cancer. This can occur through a variety of mechanisms, including changes in gene dosage and the generation of fusion genes. In recent years, it is becoming increasingly clear that these events also can alter how genomes are organized in 3D space in the nucleus and contribute to changes in enhancer-promoter regulation. However, it remains poorly understand how often 3D genome structural changes occur in cancers, what genes are affected by these events, and in which tumor types. This study is part of ongoing work to better characterize 3D genome structural changes across a variety of tumor types to better understand where and when 3D genome structure changes as the result of structural variation in cancer genomes and to characterize the genes and tumor types affected.

Study phs003227

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

National Institutes of Health The Cancer Genome Atlas (TCGA)

The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are both part of the National Institutes of Health, U.S. Department of Health and Human Services. TCGA projects are organized by cancer type or subtype. Click here for a current list of cancer types selected for study in TCGA. Data from TCGA (e.g., gene expression, copy number variation and clinical information), are available via the Genomic Data Commons (GDC). Data from TCGA projects are organized into two tiers: Open Access and Controlled Access. Open Access data tier contains data that cannot be attributed to an individual research participant. The Open Access data tier does not require user certification. Data in Open Access tier are available in the TCGA Data Portal. Controlled Access data tier contains individual-level genotype data that are unique to an individual. Access to data in the Controlled Access data tier requires user certification through dbGaP Authorized Access. Controlled Access data types consist of the following: Individual germline variant data (SNP .cel files) Primary sequence data (.bam files), which are available at GDC Clinical free text fields Exon Array files (for Glioblastoma and Ovarian projects only) NOTE: TCGA strives to release most data in the open access tier. Individual genotype or sequence files are prominent exceptions. Commonly requested files such as descriptions of somatic mutations or clinical data are open access. Please go to this page: https://tcga-data.nci.nih.gov/docs/publications/ to access all data associated with TCGA tumor specific publications. The TCGA study is utilized in the following dbGaP substudies. To view genotypes and other molecular data collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000178 TCGA study. phs000854 Genome-wide Analysis of Noncoding Regulatory Mutations in Cancer

Study phs000178

GECCO: Detecting Common and Rare Genetic Loci and GxE Interactions in Colorectal Cancer

COLON, Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life: The COLON study is a multi-center prospective cohort study to assess the role of diet and other lifestyle factors in cancer recurrence and survival among incident colorectal cancer patients in the Netherlands. DACHS, Darmkrebs: Chancen der Verhütung durch Screening:This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. EPIC, European Prospective Investigation into Cancer: EPIC is an on-going multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors and various types of cancer. HPFS, Health Professionals Follow-up Study: HPFS is a parallel prospective study to the NHS. The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Follow-up evaluation has been excellent, with 94% of the men responding to date. NHS, Nurses' Health Study: The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures [PMID:248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. NQplus, Nutrition Questionnaires plus: NQplus is a longitudinal observational study on diet and health in the general Dutch population.

Study phs001315

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