Search Results - EGA European Genome-Phenome Archive

TIGER-LC OncoVar Sequencing

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We performed targeted sequencing of Thai ICC and HCC among the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) cohort using the OncoVar platform.

Study phs001199

OncoArray: Oral and Pharynx Cancer

Genetic factors play an important role in susceptibility to head and neck cancer and could also explain differences in response to treatment and outcome. The goal of this project is to investigate genetic variation involved in oral and oropharyngeal cancer susceptibility by performing the largest GWAS on these diseases, using a novel genotyping tool specifically designed for cancer studies by the OncoArray Network. This project encompasses data from approximately 6000 oral and pharynx cancer cases and 4000 controls derived from 12 epidemiological studies most of case-control design. The genotyping was centralized at the Center for Inherited Disease Research (CIDR), and the epidemiological data harmonization and analysis were completed at the International Agency for Research on Cancer (IARC). This study was supported by National Institute of Dental and Craniofacial Research (NIDCR) with direct funding to CIDR.

Study phs001202

Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET)

STARNET is a genetics of RNA expression study of multiple disease-relevant tissues obtained from living patients with cardiovascular disease. Tissue samples are obtained from blood, atherosclerotic-lesion-free internal mammary artery (MAM) and atherosclerotic aortic root (AOR), subcutaneous fat (SF), visceral abdominal fat (VAF), skeletal muscle (SKLM), and liver (LIV) during open thorax surgery of 600 coronary artery disease (CAD) patients. All patients gave written informed consent. The inclusion criterion was eligibility for coronary artery by-pass graft (CABG) surgery. Patients with other severe systemic diseases, such as active systemic inflammatory disease or cancer, were excluded. The primary clinical end points were the SYNTAX score based on the extent of coronary atherosclerosis assessed from preoperative angiograms. The STARNET patients are Caucasians (31% females); 32% had diabetes, 75% had hypertension, and 67% had hyperlipidemia; and 33% had an MI before age 60. By New York Heart Association criteria, 45% were class I, 42% class II, 9% class III, and 1% class IV. TYPES AND RNA SEQUENCING: 566 DNA genotype and 3577 RNA-seq profiles from seven tissues from 600 STARNET CABG patients passed quality control (on average 511 RNA-seq profiles/tissue). DNA was genotyped with the OmniExpress Exome array (Illumina, ~900k SNPs) and imputed to a total of 14,098,063 DNA variant calls (6,245,505 with minor allele frequency >5%). The STARNET subjects mainly overlap with Caucasian of Northern European (Finnish) descent. RNA sequencing was performed using the HighSeq2000 platform, poly-A (LIV, SKLM, VAF, SF and blood) and ribo-zero (AOR, MAM) protocols with 50-100 bp read lengths, single end to 15-30 million read depth.

Study phs001203

National Cancer Institute (NCI) Study of Lung Cancer and Smoking Phenotypes in African-American Cases and Controls

This is a two-stage case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The stage 1 studies included 1737 cases and 3602 controls from the following studies: MD Anderson Lung Cancer Epidemiology Study, The Multiethnic Cohort Study (MEC), NCI-MD Lung Cancer-Case Control Study, Northern California Lung Cancer Study, Project CHURCH (Creating a Higher Understanding of Cancer Research δ Community Health), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), Southern Community Cohort Study (SCCS), and the Karmanos Cancer Institute at Wayne State University (KCI/WSU). The stage 2 studies included an independent set of 866 cases and 796 controls from the following studies: The Black Women's Health Study (BWHS), The Harvard-MGH Lung Cancer Susceptibility Study (HLCS), MD Anderson Lung Cancer Epidemiology Study, MD Anderson/LBJ Hospital Biorepository, NCI-MD Lung Cancer Case-Control Study, Northern California Lung Cancer Study, Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene), Southern Community Cohort Study (SCCS), and KCI/WSU.

Study phs001210

Evaluation of Ancestry Admixture among Chileans

The purpose of this study is to investigate ancestry admixture among Chileans with and without gallbladder cancer.

Study phs001385

NHLBI TOPMed: Genetic Study of Atherosclerosis Risk (GeneSTAR)

GeneSTAR began in 1982 as the Johns Hopkins Sibling and Family Heart Study, a prospective longitudinal family-based study conducted originally in healthy adult siblings of people with documented early onset coronary disease under 60 years of age. Commencing in 2003, the siblings, their offspring, and the coparent of the offspring participated in a 2 week trial of aspirin 81 mg/day with pre and post ex vivo platelet function assessed using multiple agonists in whole blood and platelet rich plasma. Extensive additional cardiovascular testing and risk assessment was done at baseline and serially. Follow-up was carried out to determine incident cardiovascular disease, stroke, peripheral arterial disease, diabetes, cancer, and related comorbidities, from 5 to 30 years after study entry. The goal of several additional phenotyping and interventional substudies has been to discover and amplify understanding of the mechanisms of atherogenic vascular diseases and attendant comorbidities.

Study phs001218

Detection of Genes Predisposing to Hematologic Malignancies

We have been conducting genetic studies on families at high risk of different hematologic malignancies, in order to define the related tumors in the families, define precursor and other related conditions, and map and identify susceptibility genes. We have focused mainly on four types of lymphoid malignancies: chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and Waldenström macroglobulinemia (WM). A few families with a rare lymphoma subtype, hairy cell leukemia (HCL) are included. In addition, single large pedigrees with acute myeloid leukemia (AML), and juvenile myelomocytic leukemia (JMML) are included. Families are ascertained for having at least two patients with the same hematologic malignancy and are classified by the type of malignancy that predominates in the family. Multiple types of lymphoid malignancies are often found in the same family. Other data has shown that these conditions aggregate together in families. Verification of cancer diagnoses is obtained through medical records, pathology reports, and flow cytometry. Family members with precursor traits are also included, monoclonal B-cell lymphocytosis (MBL) in CLL families and IgM monoclonal gammopathy of undetermined significance (MGUS) in WM families.

Study phs001219

ProHealth: Kaiser Permanente Genome-wide Association Study of Prostate Cancer

A genome-wide association study (GWAS) of prostate cancer (PCa) was conducted in Kaiser Permanente (KP) Northern California health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) [PMID: 26034056]. The data for these members were drawn from three KP cohort studies: Research Program in Genes, Environment and Health (RPGEH) ProHealth, and California Men's Health Study (CMHS) (described further under Study History). Four custom arrays were designed for genotyping, one for each of the four major race-ethnicity groups in the RPGEH cohort: African Americans, East Asians, Latinos, and Non-Hispanic Whites. The number of SNPs and SNP content varied by array, with SNP content designed to maximize the genome-wide coverage of low frequency and more common variants specific to the different race-ethnicity groups, including newly identified SNPs from sequencing projects, and SNPs with established associations with disease phenotypes and risk factors [PMIDs: 21565264, 21903159]. Within the total study cohort, n=34,736 completed a consent which permitted deposition of data to NIH. Genotyping followed the same general procedure described in [PMIDs: 26092718, plus additional quality control (QC) steps for the additional men, in order to control for potential batch and kit effects, described in [PMID: 26034056. Briefly, we first repeated the filters described in [PMID: 26092718] for all four arrays (EUR, LAT, EAS, AFR). Then, on an array-wise basis, we removed SNPs with MAF<0.01, with a call rate<95%, or with Hardy-Weinberg Equilibrium (HWE) p-value in homogeneous groups<1x10ˆ-5. Furthermore, on the EUR array, to adjust for potential kit effect, we conducted a GWAS of kit, and removed those kit associated SNPs with p<1x10ˆ-6; we also re-genotyped each of the new samples (those not genotyped with the original GERA data) with some of the original GERA data, and removed SNPs with >13/1,268 (1%) mismatches. For the AFR array, to adjust potential plate batch issues, we conducted a GWAS of whether an individual was in the original GERA data vs. in the newly genotyped data and removed those batch-associated SNPs with p<0.05 (we used a stronger threshold than that used for the EUR array because there were fewer individuals on the AFR array); we also re-genotyped each of the new samples with the original GERA data and removed SNPs with >2/78 (2.6%). After the QC described above, imputation was performed as described in [PMID: 26034056]. Imputation was performed on an array-wise basis, pre-phasing with SHAPE-IT v2.5 [PMID: 22138821], and imputing from the 1000 Genomes Project October 2014 release as a cosmopolitan reference panel with IMPUTE2 [PMID: 22384356]. In addition to the GWAS described above, a nested exome-wide association study (EWAS) of PCa was also conducted (7,489 cases, 7,323 controls; 78% non-Hispanic white, 9% African-American, 3% East Asian, 6% Latino, 4% Other). A custom EWAS array primarily focused on rare variants was designed for genotyping that complemented the GWAS arrays [PMID: 26034056]. The EWAS array content included missense and loss-of-function mutations, and rare exonic mutations from The Cancer Genome Atlas (TCGA) and dbGaP prostate cancer tumor exomes [PMID: 26544944; PMID: 26544944]. Much of the EWAS array design content overlapped with the probesets on the UK Biobank Affymetrix Axiom array [PMID: 30305743]. Genotyping and QC steps taken to filter out samples exhibiting low quality and variants with low call rates are described in Emami et al., 2020 [biorXiv]. The resulting EWAS array genotypes are provided here.

Study phs001221

Centers for Common Disease Genomics (CCDG) - Whole Genome Sequencing in Type 1 Diabetes (T1DGC)

The Type 1 Diabetes Genetics Consortium (T1DGC) was established to collect resources (biological samples and data) and conduct research to better understand the genetic basis of type 1 diabetes (T1D). Collection was initiated by ascertaining affected sib-pair families (both parents, two affected siblings and, when available, an unaffected sibling), collected from five geographic regions through four recruitment networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, the T1DGC collected trio families (both parents and affected child) and cases and controls from low-prevalence populations (African-American, with four grandparents self-reporting as African ancestry; Mexican-American, with four grandparents self-reporting as ancestry from Mexico). The T1DGC also served as a repository for contributed collections from other studies, all meeting the broad data-sharing policy of the T1DGC, for inclusion in the genetic studies. These collections include T1D case samples ascertained from the UK Genetic Resource Investigating Diabetes (UK GRID) cohort, SEARCH for Diabetes in Youth (SEARCH), The Genetics of Kidneys in Diabetes (GoKinD), and control samples obtained from the British 1958 Birth Cohort, the UK National Blood Services collection, CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis), the New York Cancer Project (NYCP), and other cohorts. For the NHGRI-funded Centers for Common Disease Genomics (CCDG) project, participants with T1D and ancestry-matched controls were identified through the T1DGC, either through direct ascertainment or by contribution from other sources to the T1DGC. As the CCDG has focused initially on non-Caucasian populations for whole genome sequencing, T1DGC participants of African, Mexican and Asian ancestry (targeting ~1200 cases and ~1200 controls in each ancestral group) and a small group of participants of Northern European ancestry (~100 cases, ~100 controls) were to be contributed to the study. Whole genome sequencing of T1DGC samples would be conducted at Washington University McDonnell Genome Institute and based upon matching case-control status within an ancestry group and prioritization by the CCDG.

Study phs001222

Analysis of AR Gene Rearrangements in Prostate Cancer

Molecularly-targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signaling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumors. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class, and sub-clonal enrichment in tumors within and between patients. Despite this heterogeneity, one common outcome in tumors with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signaling in CRPC.

Study phs001223

Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

Study phs001228

Targeted Sequencing of Primary ER-positive Breast Tumors Treated with 5 Years of Tamoxifen

Targeted massively parallel sequencing analysis was conducted on DNA extracted from archived 22-28 year old, formalin-fixed primary breast tumors from 625 patents from British Columbia treated with five years of adjuvant tamoxifen monotherapy and followed for over 10 years. Genes were selected for targeted sequencing by review of existing large-scale breast cancer sequencing studies and breast cancer literature. In total, 83 genes were identified and 3,029 probes were designed to tile across all known exons. Illumina sequencing libraries were constructed, indexed, pooled, and enriched for target sequences by hybrid-capture followed by sequencing of paired-end 100bp reads. All samples met minimum quality controls of 80% targeted space covered at 20X or greater. On average, each sample had 336M aligned bases and a mean coverage of 135.8X.

Study phs001234

Integrative Analysis of Lung Adenocarcinoma in EAGLE (Phase 2)

We performed whole genome sequencing and whole exome sequencing of 31 lung adenocarcinoma (LUAD) samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study.

Study phs001239

Genetic Basis of Breast Cancer Resistance in BRCA1 Mutation Carrier

Our study addressed a specific question in NCI RFA-CA-12-022: "What underlying causal events - e.g., genetic, epigenetic, biologic, behavioral, or environmental - allow certain individuals to survive beyond the expected limits of otherwise highly lethal cancers?". A germline mutation in BRCA1 (BRCA1+) is the most penetrant genetic predisposition for breast cancer. Nevertheless, a portion of BRCA1+ carriers does not develop breast cancer in their lifetime, suggesting that the genetic predisposition can be antagonized by resistant factors. BRCA1+ was inherited from an ancestor of the carrier family thousand years ago. We hypothesize that evolution could select certain genetic components to suppress oncogenesis caused by the predisposition. We compared germline variants in all genes in 27 pairs of breast cancer-unaffected and -affected BRCA1+ carriers, each pair inherited the same BRCA1+. We identified 12 deleterious variants enriched in breast cancer-unaffected carriers, all are common variants. A variant rs3735400 is located in ANLN, a cytokinesis-essential gene. Overexpression of variant-containing ANLN and suppressed expression of endogenous ANLN decrease ANLN nuclear localization and delay cell growth. Our findings suggest that common variants can be selected to resist oncogenesis imposed by BRCA1+.

Study phs001243

Nasopharynx Cancer Whole Exome Sequencing

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression, and rational therapy design. Here, we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway in a total of 41% of cases including CYLD, TRAF3, NFKBIA and NLRC5. Functional analysis confirmed novel inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent member protein 1 (LMP1) functions to constitutively activate NF-kB signaling, and we observed mutual exclusivity among somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

Study phs001244

GMKF: Kids First Pediatric Research Program on Congenital Cranial Dysinnervation Disorders and Related Birth Defects

The Gabriella Miller Kids First Pediatric Research Program (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). Both, childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Goals of this ongoing study are to identify novel "congenital cranial dysinnervation disorder" (CCDD) genes and define the role of the wildtype and mutant genes in normal and aberrant development. The umbrella term (CCDD) refers to congenital birth defects with malformation of one or more cranial nerves, typically resulting in limitations of eye and/or face movement. Examples of CCDDs include congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, Duane retraction syndrome (DRS), horizontal gaze palsy with progressive scoliosis (HGPPS), congenital 3rd, 4th or 6th nerve palsies, Moebius syndrome (MBS), and hereditary congenital facial paresis (HCFP). In some cases, anosmia, and disorders of hearing, sucking, chewing, swallowing, and breathing may also be classified as CCDDs. CCDDs can be accompanied by additional birth defects such as intellectual and social disabilities, developmental delays, limb anomalies, and cardiac, GI, and GU disorders. The genetic basis of multiple CCDDs has been determined, and the gene mutations typically alter cranial motor neuron identity or function, or perturb axon growth and guidance. Despite these successes, the genetic etiologies of many inherited CCDDs remain unidentified.

Study phs001247

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