Search Results - EGA European Genome-Phenome Archive

Clinical Sequencing Exploratory Research (CSER): Clinical sequencing in cancer: Clinical, ethical, and technological studies

The Clinical Sequencing Exploratory Research (CSER) program supports multi-disciplinary projects that bring together clinicians, bioinformaticians, and ethicists to research the challenges of utilizing genomic sequence data in the clinic in the routine practice of medicine. The challenges are many and not disease-specific. Important aims of the research include: development of technical specifications and standards for sequencing in a clinical setting, investigation of methods to transmit genome-scale data to physicians in a fashion and timescale that fits the normal clinical workflow, exploration of regulatory requirements for applying genomic sequence data to patient care, study of physician and patient preferences regarding presentation of genomic information, and study of the ethical implications of returning unanticipated findings. More information about CSER and the investigators and institutions who comprise the CSER consortium can be found at http://www.genome.gov/27546194. The NEXT (New Exome Technology) Medicine Study utilizes a randomized controlled trial (RCT) structure to compare usual care (UC) practice in Medical Genetics Clinics with the introduction of a powerful research tool of whole exome sequencing plus UC practices for Colorectal Cancer and Polyposis (CRCP) in adults. In doing so, the study aims to explore the practical, economic, and ethical implications of identifying and returning incidental findings ("extra" whole exome genetic risk results not associated with CRCP that includes pharmacogenetic variants) to patients. The study will also attempt to identify novel causal genes for CRCP by studying relatives of selected research subjects.

Study phs000999

Research Program on Genes, Environment and Health (RPGEH)

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (≥ 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants' electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men's Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

Study phs000788

North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the UNC Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are included here. The third study release includes data of additional n=189 subjects.

Study phs000827

Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities

The Platinum Study is an R01-funded, multicenter study of testicular cancer survivors that characterizes both long-term cisplatin-induced peripheral neuropathy (CisIPN) and cisplatin-associated ototoxicity, i.e., permanent, bilateral hearing loss. We collected data abstracted from medical records (e.g., cumulative cisplatin dose), conducted audiometric examinations, and administered self-report questionnaires, which included CisIPN symptoms.

Study phs001621

Genome-Wide Association Studies in Upper Gastrointestinal Cancers (Asian)

This project aims to conduct genome-wide association studies (GWAS) in two anatomically different upper gastrointestinal (UGI) cancer sites in two populations with distinctly different disease rates and genetic profiles. One population has very high rates for both esophageal squamous cell carcinomas (ESCCs) and gastric cancers (GCs) and is comprised of Asians (the "Asian UGI GWAS"), while the other population has low rates of ESCC and GC and includes non-Asians from the Americas, Europe, and Australia (the "Non-Asian UGI GWAS"). Study participants for the Asian UGI GWAS reported here (Illumina 660W Quad chip) were drawn from 2 studies, the Shanxi Upper Gastrointestinal Cancer Genetics Project (Shanxi) and the Linxian Nutrition Intervention Trial (NIT), a prospective cohort, and included a total of 1898 ESCCs, 1625 GCs, and 2100 controls. For the 2nd phase (8 TaqMan SNPs), additional subjects from Shanxi and NIT as well as subjects from the Shanghai Men's Health Study (SMHS), the Shanghai Women's Health Study (SWHS), and the Singapore Chinese Health Study (SCHS) were also included (217 ESCCs, 615 GCs, 1202 controls). Altogether 2115 ESCCs, 2240 GCs, and 3302 controls were genotyped in this study.

Study phs000361

Optimized Polyepitope Neoantigen DNA Vaccines Elicit Neoantigen-Specific Immune Responses in Preclinical Models and in Clinical Translation

A patient with Lynch syndrome and a neuroendocrine tumor sequenced with exome, whole genome, and bulk RNAseq. Sequence data was used to create a personalized cancer vaccine.

Study phs002342

Genome-Wide Association Study of HCC in Non-Asian USA Population

This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy <12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

Study phs001744

Germ Cell and Associated Heme Malignancies Evolve from a Common Shared Precursor

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15-40. While most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal non-seminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggests a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals has not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of fifteen patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced TP53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor which gives rise to the parallel evolution of GCTs and blood cancers in these patients. Reprinted from PMID: 32897884, with permission from JCI.

Study phs002231

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

PD-1 Instructs a Tumor Suppressive Metabolic Program to Restrain AP-1 Activity in T Cell Lymphoma

T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of aggressive cancers of mature CD4+ T cells, for which therapeutic options are limited. Recent work uncovered that the PDCD1 encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells. PD-1 is recurrently inactivated in T-NHL and the highest frequencies of PDCD1 deletions are detected in advanced disease, predicting worse prognosis. The tumor-suppressive mechanisms of PD-1 signaling remain unknown. In the present study, we identify transcriptional and epigenetic mechanisms underlying PD-1 tumor suppression in T-NHL.Some subjects included in this study overlap with the subjects from phs002456. To establish the link between the overlapping subjects, the Subject Consent datasets will be utilized.

Study phs003312

Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

Biopsies of castration resistant prostate cancer metastases were subjected to whole genome sequencing (WGS), along with RNA-sequencing (RNA-Seq). The overarching goal of the study is to illuminate molecular mechanisms of acquired resistance to therapeutic agents, and particularly androgen signaling inhibitors, in the treatment of metastatic castration resistant prostate cancer (mCRPC).

Study phs001648

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

Drug screening of patient-derived organoids from colorectal peritoneal metastases

Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We trialed the possibility of organoid directed precision treatment for CRPM patients. CRPM organoids (peritonoids) isolated from patients underwent next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. In conclusion, our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Study phs002023

Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

Study phs001660

Kids First: Genomic Studies of Orofacial Cleft 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). 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. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

Study phs001168

A Genome Wide Scan of Lung Cancer and Smoking

The majority of cases of lung cancer are the culmination of a dynamic process that begins with smoking initiation, proceeds through dependency and smoking persistence, continues with lung cancer development and ends with progression to disseminated disease or response to therapy and survival. We are conducting a whole genome study of lung cancer and smoking to examine critical steps in lung cancer progression. This study is a genome-wide association study (GWAS) to investigate the genetic determinants of lung cancer risk. The study design efficiently allows identification of genes that also contribute to smoking persistence and outcome from lung cancer using a single GWAS of 5,900 subjects using the primary GENEVA dataset, derived from two studies. The first is the Environment and Genetics in Lung Cancer Etiology Study (EAGLE), a population-based, biologically intensive, case-control study from the Lombardy region of Italy including ~2000 newly diagnosed lung cancer cases and ~2000 age-, gender- and region- matched controls. The second is the Prostate, Lung, Colon and Ovary Study (PLCO) Cancer Screening Trial from which we have selected ~850 lung cancer cases and ~850 controls, also matched on age and gender. Understanding the basis for the well-established hereditary component of lung cancer and smoking persistence could provide new insights into etiology, prevention, and treatment, and have an enormous impact on public health. The same GWAS genotyping data in the two studies will be used to investigate the genetic determinants of smoking persistence. Specifically, we will analyze current smokers and former smokers from EAGLE and PLCO for diverse smoking phenotypes, including persistence of smoking as well as ever/never smoking comparisons, quitting attempts, and the Fagerström index of tobacco addiction. PLCO participants are all European-Americans and EAGLE involves subjects from Italy. EAGLE is a case-control study and contains 3937 phenotyped subjects. PLCO is a screening trial with a cohort design and contains 1651 phenotyped subjects. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to lung cancer and smoking through large-scale genome-wide association studies of population-based samples of lung cancer cases and controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000093

Genomic Correlates of Response and Resistance to Immune Checkpoint Blockade in Solid Tumors

Immune checkpoint inhibitors yield clinical benefit in many cancer types, but molecular predictors of response have not yet been robustly characterized. In this study, we pursued whole exome sequencing (WES) of pre-treatment tumors from patients treated with immune checkpoint therapies - including monoclonal antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Using these data, we aim to apply computational pipelines for mutation-calling, neoantigen prediction, and other analyses to validate pre-existing hypotheses regarding response to immune checkpoint therapies and discover new relationships with greater power. Further, by pursuing genomic characterization of tumors from patients with a variety of cancer types, we hope to describe molecular features of intrinsically sensitive or resistant tumors that are both context-specific and shared across cancer types.

Study phs001565

Transdisciplinary Research Into Cancer of the Lung (TRICL) - Exome Plus Targeted Sequencing

The study was conducted under the auspices of the Transdisciplinary Research In Cancer of the Lung (TRICL) Research Team, which is a part of the Genetic Associations and MEchanisms in ONcology (GAME-ON) consortium, and associated with the International Lung Cancer Consortium (ILCCO). Ethics All participants provided written informed consent. All studies were reviewed and approved by institutional ethics review committees at the involved institutions. Sequencing data are derived from four sub-studies. The sub-studies that contributed include Harvard, Liverpool, Toronto, and IARC. The IARC and Toronto studies are described above. A description of the Harvard and Liverpool studies is provided below. Liverpool Lung Project: The Liverpool Lung Project (LLP)1 is a case control and cohort study, which has over 11,500 individuals, with detailed epidemiological, clinical and outcome data with associated specimens (i.e. tumour tissue, blood, plasma, sputum, bronchial lavage, EBUS and oral brushings). The participants have completed a detailed lifestyle questionnaire and updated data on clinical outcome and hospital events are collected through the Office of National Statistics, Cancer Registry and from Health Episode Statistics. The project is registered on the UK National Institute for Health Research (NIHR) lung cancer portfolio and has all the required ethical approvals and sponsorship arrangements in place. The LLP has detailed standard operating procedures (SOP) for all aspects of the recruitment, data, specimen collection as well as the data storage. The LLP Cohort study has 8,224 participants with blood and 7,761 with plasma samples. The LLP case-control samples have been incorporated into in a large number of international GWAS and molecular studies 2,3, methylation 4-7, microRNA 8and next generation studies 9-11, resulting in high ranking publications, as well as forming the basis for the LLP risk prediction model 12-14 which has been utilised in the UK lung cancer screening trial (UKLS) 15-17 Patient and control DNAs were derived from EDTA-venous blood samples. Harvard Samples. David Christiani at the Harvard University School of Public Health has been directing research studies to investigate etiological factors influencing lung cancer development since 1983 and has amassed a collection of 2000 controls and 5055 lung cancer cases. He has been actively collecting and storing snap frozen tumor samples since 1992. Around 1500 tumor samples have been collected and the average wet tumor yield is about 30 grams of tumor, of which 631 cases have completely annotated clinical and survival information. Pathology confirmation is provided by two pathologists. At the time of surgery, a minimum of 30 grams of wet lung tumor tissue and 30 grams of non-involved tissue from the same lobe is sectioned, flash frozen and sent to Dr. Christiani's lab for logging and storage. A blood sample for DNA and serum is collected. A structured interview by trained research staff is conducted on each case, and clinical outcomes and treatments is extracted and entered into the molecular epidemiology data base at Harvard. Fresh frozen samples have been collected from 1451 lung cancer and are available for study. Samples from this collaborative study have played key roles in major studies, including the initial finding describing EGFR mutations in lung cancer 22. Participants in this study are patients, > 18 years of age, with newly diagnosed histologically confirmed lung cancer. Samples that are included in the analysis have the following histologies: Adenocarcinoma: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3 8560/3; LCC: 8012/3, 8031/3; squamous carcinoma: 8070/3, 8071/3, 8072/3, 8074/3; and other NSCLC: 8010/3, 8020/3, 8021/3, 8032/3, 8230/3. The Toronto Study: The Toronto study was conducted in the Great Toronto Area between 1997 and 2014. Cases were recruited at the hospitals in the network of University of Toronto and Lunenfeld- Tanenbaum Research Institute. At the time of recruitment in the clinical setting, provisional diagnoses of lung carcinoma were first assigned based on clinical criteria. Diagnoses for all cases included were histologically confirmed by the reference pathologist who is a specialist in pulmonary pathology, based on review of pathology reports from surgery, biopsy or cytology samples in 100% of cases. Diagnostic classification was done initially according to ICD-9, ICD-10, and ICD for oncology-2, and subsequently converted to ICD-O-3. Tumors were grouped into the major categories included in this analysis according to primary cancer type based on the ICD-3 definitions. Controls were randomly selected from individual visiting family medicine clinics and Ministry of Finance Municipal Tax Tapes. All subjects were interviewed using a standard questionnaire and information on lifestyle risk factors, occupational history, medical and family history was collected. Blood samples were collected from more than 85% of the subjects. IARC: The IARC data are derived from case-control studies conducted in Russia and include samples that have available tissue samples. Patient and control DNAs were derived from EDTA-venous blood samples. The lung cancer patients were classified according to ICD-O-3; SQ: 8070/3, 8071/3, 8072/3, 8074/3; AD: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3, 8560/3, 8251/3, 8490/3, 8570/3, 8574/3; with tumous with overlapping histologies classified as mixed. The Lung Cancer Transdisciplinary Research Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000876 Lung Cancer Transdisciplinary Research Cohort. phs000877 Meta Analysis phs000878 CIDR Lung Cancer phs001681 Affy Axiom Array

Study phs000876

Comprehensive Genomic Characterization of Acral Melanoma

In this study, we performed paired tumor/normal long insert whole genome and exome sequencing and tumor RNA sequencing on primary or metastatic acral melanoma tumors collected from 34 patients. Patients were enrolled from either Vanderbilt University or the Memorial Sloan-Kettering Cancer Center. We report an integrated analysis of DNA and RNA sequencing data to describe genomic and transcriptomic characteristics of acral melanoma.

Study phs001036

Oncoarray Consortium - Lung Cancer Studies

The study was conducted under the auspices of the Transdisciplinary Research In Cancer of the Lung (TRICL) Research Team, which is a part of the Genetic Associations and MEchanisms in ONcology (GAME-ON) consortium, and associated with the International Lung Cancer Consortium (ILCCO). Ethics: All participants provided written informed consent. All studies were reviewed and approved by institutional ethics review committees at the involved institutions. Sequencing data are derived from four substudies. The substudies that contributed include Harvard, Liverpool, Toronto, and IARC. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study is a randomized primary prevention trial including 29,133 male smokers enrolled in Finland between 1985 and 1993. Participants ranged between ages of 50 to 69 at enrollment and were randomized in a factorial design to take either 50 milligrams of d-alpha tocopheryl acetate (Vitamin E), 20 mg of all-trans-beta-carotene, both or placebo. The study continued to monitor cancer incidence through 2012 and total mortality through December 2013. The CAncer de PUlmon en Asturias Study (CAPUA) is a hospital-based case-control study conducted in Asturias, Spain by the University of Oviedo. Lung cancer cases were recruited in three main hospitals of Asturias, following an identical protocol from 2002 to 2012. Eligible cases were incident cases of histologically confirmed lung cancer between 30 and 85 years of age and residents in the geographical area of each participating hospital. Controls were selected from patients admitted to those hospitals with diagnoses unrelated to the exposures of interest and individually matched by ethnicity, gender, age (± 5 years) and hospital. Epidemiologic data were collected personally through computer-assisted questionnaires by trained interviewers during the first hospital admission. Structured questionnaires collected information on sociodemographic characteristics, recent and prior tobacco use, environmental exposure (air pollution and passive smoking), diet, personal and family history of cancer, and occupational history from each participant. Peripheral blood samples (or mouthwash samples when they refused to donate blood) were collected from all participants. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The Canadian Screening Study includes the nested case-control samples from 3 screening programs: IELCAP-Toronto: Ever smokers of more than 10 pack-years age 50 and above were eligible for the I-ELCAP screening program since 2003, and a total of 4782 individuals have been enrolled in the Greater Toronto Area. Participants were administered a LDCT scan along with a standard study questionnaire at baseline. Blood samples were systematically collected at baseline since 2006. Participants who had an abnormality in a CT scan were followed up every 1 to 2 years. The screening program was organized by the Princess Margaret Hospital. PanCan: Ever smokers between the ages of 50-75 with no previous history of invasive cancer are eligible to participate in the study. The study was carried out across Canada in Vancouver, Calgary, Hamilton, Toronto, Ottawa, Quebec, Halifax, and St. John's. A total of 2537 smokers have been screened from 2008 to 2011. All study participants completed a detailed questionnaire, spirometry, collection of blood specimens for biomarker measurement and LDCT at baseline. All participants are followed for a minimum of 3 years. On yearly follow up, an updated shorter questionnaire is administered, blood is collected and CT scans are performed. Blood samples are available from all 2537 individuals. BCCA Screening Program: From 1990 to 2007, 4274 smokers above 40 years old who had smoked 20 pack-years or more were enrolled at BCCA. Upon enrollment, subjects completed a questionnaire for their lifestyle and medical history. Baseline spirometry was conducted using a flow-sensitive spirometer in accordance with the American Thoracic Society recommendations. Since 2000, a LDCT was obtained in 2440 individuals. The participants were followed prospectively to determine whether they developed lung cancer. A total of 9759 individuals participated in the CT screening program in Canada from these 3 programs. The samples included in this project is based on a subset of nested lung cancer case-control pairs based on 1:2 ratio. The Carotene and Retinol Efficacy Trial (CARET) was a randomized, double-blind, placebo-controlled trial of the cancer prevention efficacy and safety of a daily combination of 30 mg of beta-carotene and 25,000 IU of retinyl palmitate in 18,314 persons at high risk for lung cancer. CARET began in 1985, and the intervention was halted in January 1996, 21 months ahead of schedule, with the twin conclusions for definitive evidence of no benefit and substantial evidence of a harmful effect of the intervention on both lung cancer incidence and total mortality. CARET continued to follow and collect endpoints on their participants through 2005. Pathology reports and medical records were reviewed to confirm cancer endpoints, and death certificates obtained to capture cause of death. During the active intervention phase of CARET, serum, plasma, whole blood, and lung tissue specimens were collected on participants. These biospecimens make up the CARET Biorepository. For the OncoArray Project, CARET provided DNA extracted from whole blood of lung cancer cases and controls matched on age at baseline (± 4 years), sex, race, baseline smoking status, history of occupational asbestos exposure (asbestos vs heavy smoker), and year of enrollment (2-year intervals). The European Prospective Investigation into Cancer and Nutrition (EPIC) study is a multi-center cohort study involving 521,000 study participants from 10 European countries. The current study involved EPIC participants from 7 countries (Greece, Netherlands, UK, France, Germany, Spain, and Italy), including 1223 incident lung cancer cases and 1249 smoking matched controls. The Kentucky Lung Cancer Research Initiative is a study conducted by the Markey Cancer Center Cancer Center and the University of Kentucky using a population-based, case-control framework to study the extraordinarily high rates of lung cancer in Southeastern, Appalachian Kentucky. Cancer cases were recruited from the Kentucky Cancer Registry at the time of diagnosis and controls were recruited from a random digit dialing process from the same region. Study accrual began in January 5, 2012 and completed on September 5, 2014 and 520 subjects were recruited in a 4:1 ratio of controls: cases from Appalachian Kentucky. Of the 520 subjects recruited, 231 are included in the OncoArray analysis, including all 93 cancer cases, and 123 controls. Newly diagnosed lung cancer cases and controls underwent blood, toenail (for trace element analysis), urine, buffy coat, water, soil, and radon collection, residence GPS mapping, as well as an extensive epidemiologic, occupational, and health history questionnaire (Clinical Trials.gov Identifier: NCT01648166). The Harvard Lung Cancer Study (HLCS) is a case-control study based at Mass General Hospital (MGH) in Boston, Massachusetts from 1992 to 2004. Details of the study were described previously. Briefly, eligible cases included any person over the age of 18 years with a diagnosis of primary lung cancer that was further confirmed by an MGH lung pathologist. Controls were recruited from the friends or spouses of cancer patients or the friends or spouses of other surgery patients in the same hospital. Potential controls were excluded from participation if they had a diagnosis of any cancer (other than non-melanoma skin cancer). Interviewer-administered questionnaires, a modified version of the standardized American Thoracic Society respiratory questionnaire, collected information on demographics, medical history, family history of cancer, smoking history, and a detailed work history, including job titles and tasks. Genome-wide genotype data were first generated using Illumina Human 610-Quad BeadChips and then imputed by MACH against the 1000 Genome Project dataset (http://browser.1000genomes.org/index.html). The Institutional Review Board of MGH and the Human Subjects Committee of the Harvard School of Public Health approved the study. The Israel study (NICCC-LCA) is an ongoing case-control study of newly diagnosed lung cancer cases of any histology and population age/sex/ethnicity-matched "healthy" controls. All participants undergo face-to-face interviews, provide a venous blood sample (separated into DNA, Sera, lymphocytes) after signing an IRB-approved form. Histology reports, FFPE blocks and clinical follow-up are available for most cancer cases. The MD Anderson Cancer Center (MDACC) Study. Lung cancer cases and frequency-matched controls were ascertained from a large ongoing case-control study at the University of Texas MD Anderson Cancer Center (UTMDACC) since 1991. Detailed study description was provided previously (Spitz et al 2007). In brief, cases were newly-diagnosed and histologically confirmed lung cancer patients recruited from UTMDACC. Controls were healthy individuals without a history of cancer (except for nonmelanoma skin cancer) and recruited from the Kelsey-Seybold Clinics, the largest private multispecialty physician group in the Houston metropolitan area. Controls were frequency-matched to cases on age (±5 years), sex, and race/ethnicity. After providing written informed consent, each study participants completed an in-person interview by staff interviewers to collect information on demographics, smoking status, etc. Blood samples were also drawn from all the study participants. This study was approved by institutional review boards of UTMDACC and Kelsey-Seybold Clinics. The Malmö Diet and Cancer Study (MDCS) is a population-based prospective cohort study that recruited men and women aged at 44 to 74 years old of living in Malmö, Sweden between 1991 and 1996. The main goal of the MDCS is to study the impact of diet on cancer incidence and mortality. It consists of a baseline examination including dietary assessment, a self-administered questionnaire, anthropometric measurements and collection of blood samples. A total of 165 incident lung cancer cases and 174 individually smoking-matched controls were available for this analysis. The Multiethnic Cohort (MEC) Study includes 215,251 men and women aged 45-74 years at recruitment, primarily from five ethnic/racial groups - African Americans and Latinos mostly recruited from CA (mainly from Los Angeles County) and Japanese Americans, Native Hawaiians and whites (mostly recruited from HI). The cohort was assembled in 1993-1996 by mailing a self-administered questionnaire to persons identified primarily through driver's license files. The baseline questionnaire obtained information on demographics, anthropometry, smoking history, medical and reproductive histories, family history of cancer, diet and physical activity. Incident cancer cases are identified by regular linkage with the State of California Cancer Registry and the Hawaii Tumor Registry, both members of the SEER Program of the NCI. In 2001-2006, a prospective biorepository was assembled by collecting a pre-diagnostic blood specimen from 67,594 surviving MEC members. At the time of blood collection a short questionnaire was administered that included information on smoking during the previous 15 days. For this study, cases were all lung cancer cases incident to blood draw and diagnosed before December 2012. For each case, a control was selected among unaffected MEC participants who were alive at time of the case's diagnosis and matched on study site, sex, race/ethnicity, age (age at diagnosis for cases; age at blood collection for controls), and date of blood collection. The Mount-Sinai Hospital-Princess Margaret Study (MSH-PMH) was conducted in the greater Toronto area from 2008 to 2013. Lung cancer cases were recruited at the hospitals in the network of the University of Toronto. Controls were selected randomly from individuals registered in the family medicine clinics databases and were frequency matched with cases on age and sex. All subjects were interviewed, and information on lifestyle risk factors, occupational history and medical and family history was collected using a standard questionnaire. Tumors were centrally reviewed by the reference pathologist, a member of the International Association for the Study of Lung Cancer (IASLC) committee, and a second pathologist in the University Health Network. If the reviews conflicted, a consensus was arrived at after discussion. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The New England Lung Cancer Study (NELCS) is a population-based case-control study of lung cancer among residents of Northern and Central New Hampshire counties and the bordering region of Vermont. Cases with histologically confirmed primary incident lung cancer were identified from 2005 to 2007 using the New Hampshire State Cancer Registry and the Dartmouth-Hitchcock Medical Center (DHMC) Tumor Registry. Control participants were identified using a commercial database and matched to lung cancer cases within 5-year age groups, sex and county. Genomic DNA was isolated from blood or buccal specimens provided by consenting participants. The study complied with requirements of the Dartmouth College's Committee for Protection of Human Subjects. The Nijmegen Lung Cancer Study. The Netherlands patients with lung cancer were identified through the population-based cancer registry of the Netherlands Comprehensive Cancer Organisation in Nijmegen, the Netherlands. Patients who were diagnosed in one of three hospitals (Radboud University Medical Center, Canisius Wilhelmina Hospital in Nijmegen, and Rijnstate Hospital in Arnhem) since 1989 and who were still alive at April 15th, 2008 were recruited for a study on gene-environment interactions in lung cancer. 458 patients gave informed consent and donated a blood sample. This case series was expanded with 94 patients to a total of 552 by linking three other studies to the population-based cancer registry in order to identify new occurrences of lung cancer among the participants of these other studies. All three other studies (i.e., POLYGENE, the Nijmegen Biomedical Study, and the Radboudumc Urology Outpatient Clinic Epidemiology Study) were initiated to study genetic risk factors for disease and participants to these studies gave general informed consent for DNA-related research and linkage with disease registries. Information on histology, stage of disease, and age at diagnoses was obtained through the cancer registry. Lifestyle information was collected through a structured questionnaire and whole blood for DNA isolation was collected by the regional thrombosis services. The cancer-free controls (46% males) were selected from participants of the "Nijmegen Biomedical Study" (NBS), an age- and sex-stratified random sample of the general population of the municipality of Nijmegen, The Netherlands. All participants provided extensive lifestyle information by structured questionnaires and blood samples for DNA isolation, serum and plasma. All controls are of self-reported European descent. The study protocols of the NBS were approved by the Institutional Review Board of the Radboudumc and all study subjects signed a written informed consent form. The Northern Sweden Health and Disease Study (NSHDS) encompasses several prospective cohorts. The current study involves participants from the Västerbotten Intervention Project (VIP), a sub-cohort within NSHDS. VIP is an ongoing prospective cohort and intervention study intended for health promotion of the general population of the Västerbotten County in northern Sweden. VIP was initiated in 1985 and all residents in the Västerbotten County were invited to participate by attending a health check-up at 40, 50 and 60 years of age. Participants were asked to complete a self-administered questionnaire including various demographic factors such as education, smoking habits, physical activity and diet. In addition, height and weight were measured and participants were asked to donate a fasting blood sample for future research. A total of 243 incident lung cancer cases and 266 individually smoking-matched controls were available for this analysis. Norway National Institute of Occupational Health Study. Early-stage NSCLC cases and healthy controls at the time of enrollment were Caucasians of Norwegian origin and were recruited from the same geographical region (Western Norway). The patients were enrolled in the study, whenever practically feasible among patients admitted for lung cancer at the Haukeland University Hospital in Bergen, Norway. The informed written consents covering analysis of molecular and genetic markers was signed by the patients prior to surgery. Only patients with histologically confirmed early-stage NSCLC were included in our study. The subjects included in this project are a subgroup recruited into the project "lung cancer genetics" at NIOH. The controls were recruited from the same geographical region of Western Norway and frequency-matched with cases on cumulative smoking dose (pack-years). Pack-years smoked [( 20 cigarettes per day) x years smoked] were calculated to indicate the cumulative smoking dose. The Cases and controls were interviewed using similar questionnaires and were categorized as never smokers, ex-smokers or current smokers. Never smokers are subjects indicating having smoked less than 100 cigarettes in their life time. Ex-smokers were defined as those having quitted at least 1 year before sampling, and current smokers were those indicating that they were smokers at the time of sampling. The project has been approved by the Regional Committee for Medical and Health Research Ethics in Southern Norway in accordance with the WMA Declaration of Helsinki. The ethical approval covered access to the NSCLC databank. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Study, a randomized trial aimed at evaluating the efficacy of screening in reducing cancer mortality, recruited approximately 155,000 men and women age 55 to 74 years from 1992 to 20014. Screening for lung cancer among participants in the intervention arm included a chest x-ray at baseline followed by either three annual x-rays (for current or former smokers at enrollment) or two annual x-rays (for never smokers); participants in the control arm received routine health care. Screening-arm participants provided data on sociodemographic factors, smoking behavior, anthropometric characteristics, medical history, and family history of cancer, as well as blood samples annually for the first 6 years of the study (baseline T0 and T1 through T5). Lung cancers were ascertained through annual questionnaires mailed to the participants, and positive reports were followed up by abstracting medical records or death certificates. Follow-up in the trial as of July 2009 was 96.7%. Patients were excluded because of missing baseline questionnaire, previous history of any cancer, diagnosis of multiple cancers during follow-up, missing smoking information at baseline, missing consent for utilization of biologic specimens for etiologic studies, or unavailability/insufficient quantity of serum or DNA specimens. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) is an ongoing study conducted in Sheffield from 2006 and due to complete recruitment in 2016. The study recruited pathologically confirmed lung cancer cases diagnosed at age 60 years or younger and family matched controls. Lung cancer cases diagnosed at ages older than 60 years were recruited if they reported a family history of lung cancer. The cases and matched controls were recruited through several major cancer treatment centers, however, the majority were recruited in North Trent. All participants completed a detailed lifestyle questionnaire which included questions about occupational exposures, education, medical history and family history of cancer and lung disease. Participants also donated blood samples for DNA extraction. The ReSoLuCENT study has been funded by the Sheffield Hospitals Charity, Sheffield ECMC and Weston Park Hospital Cancer Charity. First degree relatives were removed from the sample deposited to dbGaP. The Roy Castle Lung Study of Liverpool Lung Project (LLP) is a case-control and cohort study which has recruited over 11,500 individuals since 1996 from the Liverpool region in the UK. Detailed epidemiological and clinical data is collected with associated specimens (i.e. tumor tissue, blood, plasma, sputum, bronchial lavage and oral brushings). The participants have completed a detailed lifestyle questionnaire at recruitment, with repeat questionnaires at intervals; updated data on clinical outcome and hospital events are collected through the Health and Social Care Information Center (including Office of National Statistics mortality data, Cancer Registry and Health Episode Statistics). The project is registered on the UK National Institute for Health Research (NIHR) lung cancer portfolio and has all the required ethical approvals and sponsorship arrangements in place. The lung tumors were reviewed by the reference pathologist. The Seoul Bundang Lung Cancer Study was conducted between 2005 and 2010 to discover genetic and environmental factors related with lung cancer development. Lung cancer cases were recruited at the Seoul National University Hospital in Bundang. Controls were selected randomly from individuals participated in health check-up program and were frequency matched with cases on age and sex. All subjects were interviewed, and information on lifestyle risk factors, occupational history and medical and family history was collected using a standard questionnaire. Tumors were reviewed by the pathologists in the hospital. If the reviews conflicted, a consensus was arrived at after discussion. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The Shanghai Cohort Study (SCS) consisted of 18,244 men in Shanghai, China, who were 45-64 years old at the time of enrollment during 1986-1989. Approximately 80% of eligible men participated in the study. At the time of recruitment, each cohort subject was interviewed in-person by a trained nurse interviewer using a structured questionnaire that included background information, history of tobacco and alcohol use, current diet, and medical history. At the completion of the interview, the nurse collected a 10 ml blood and a single void urine specimen from the study participant. The buccal cell samples were collected from all surviving cohort members (~15,000) in the 2001-2002 follow-up interviews. The cohort has been followed for the occurrence of cancer and death through routine ascertainment of new cases from the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Units. To maximize the cancer findings and minimize the loss of follow-up, we contacted each surviving cohort member annually. Retired nurses visit the last known address of each living cohort member and record details of the interim health history of the cohort member. As of December 31, 2014, cumulatively 612 (3.4%) original subjects were lost to follow-up, and 574 (3.1%) refused to our continued follow-up interview. A nested case-control study of incident lung cancer cases within the Shanghai Cohort Study was used to examine the association between serum levels of vitamin B6 and other compounds in the one-carbon metabolism pathway and risk of lung cancer. Briefly, 516 lung cancer cases were identified among cohort participants with available serum samples as of 12/31/2006. For each case, we randomly selected one control subject from all cohort members who were free of cancer and alive at the time of cancer diagnosis of the index case. Controls were matched to the index case by age at enrollment (±2 years), date of biospecimen collection (±1 month) and neighborhood of residence at recruitment, and smoking status (current, former and never smokers) as established previously for other studies. For former smokers, cases and controls were further matched by years since quitting smoking (<10 vs ≥10 years). One serum vial per subject was retrieved from biorepository and all serum samples were sent to the laboratory (B-vital) for measurements. DNA samples of 250 lung cancer cases and 250 matched controls were available for the present study. The Singapore Chinese Health Study (SCHS) cohort consisted of 63,257 Chinese men and women in Singapore when they were 45-74 years old at the time of enrollment between April 1993 and December 1998. At recruitment, each study subject was interviewed in person by a trained interviewer using a structured questionnaire that emphasized current diet assessed via a validated, 165-item food frequency questionnaire. The questionnaire also requested information on demographics, lifetime use of tobacco, incense use, current physical activity, usual sleep duration, reproductive history (women only), occupational exposure, medical history, and family history of cancer. Blood or buccal cell, and spot urine samples were collected first from a random 3% sample of cohort participants in April 1994, and extended to all surviving cohort participants starting in January 2000. Overall approximately 60% of eligible cohort participants donated biospecimens. The cohort has been passively followed for death and cancer occurrence through regular record linkage with the population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths. Migration out of Singapore, especially among housing estate residents, was negligible. As of latest update, only 55 individuals from this cohort were known to be lost to follow-up due to migration and other reason. A nested case-control study of incident lung cancer cases within the Singapore Chinese Health Study was used to examine the association between serum levels of vitamin B6 and other compounds in the one-carbon metabolism pathway and risk of lung cancer. As of 12/31/2011, 422 lung cancer cases were identified among cohort participants with available prediagnostic plasma samples. For each case, one control subject was randomly selected from all eligible cohort members who were alive and free of cancer on the date of cancer diagnosis of the index case. The control subject was individually matched to the index case by gender, dialect group (Hokkien, Cantonese), age at enrollment (±3 years), date of baseline interview (±2 year), date of biospecimen collection (±6 months), and smoking status (current, former, and never smokers). For current smokers, cases and controls were further matched by number of cigarettes per day (<15, ≥15 cigarettes/day). For former smokers, cases and controls were further matched by years since quitting smoking (<10, ≥10 years). One plasma aliquot per subject was retrieved from the biorepository and all plasma samples were sent to the laboratory (B-vital) for measurements, and one aliquot of DNA per subject for the present study. The International Agency for Research on Cancer (IARC) L2 Study. Lung cancer cases and controls were recruited through a multicentric case-control study coordinated by the IARC in Russia, Poland, Serbia, Czech Republic, and Romania from 2005 to 2013. Cases were incident cancer patients collected from general hospitals. Controls were recruited from individuals visiting general hospitals and out-patient clinics for disorders unrelated to lung cancer and/or its associated risk factors, or from the general population. Information on lifestyle risk factors, medical and family history was collected from subjects by interview using a standard questionnaire. All study participants provided written informed consent. The current study included 1,133 lung cancer cases and 1,117 controls genotyped on the Oncoarray. The Washington State University Lung Cancer Study is a hospital case-control study of 511 subjects with newly-diagnosed (within 1 year of diagnosis) lung cancer and 820 race-, sex- and age-matched controls. Lung cancer cases were recruited from lung cancer clinics within the H. Lee Moffitt Cancer Center while controls were recruited from the Lifetime Cancer Screening Center, a H. Lee Moffitt Cancer Center affiliate. None of the controls were diagnosed with any form of cancer at the time of screening. Detailed questionnaire data and oral buccal cells were collected for all subjects. The Total Lung Cancer (TLC) Study is a hospital-based study that included 458 lung cancer patients recruited for Moffitt Cancer Center's Total Cancer Care™ protocol between April 2006 and August 2010. Total Cancer Care™ is a multi-institutional observational study of cancer patients that prospectively collects self-reported demographic and clinical data, medical record information and blood samples for research purposes. All patients used in this cohort were recruited from the Thoracic Oncology Clinic at the Moffitt Cancer Center. The Vanderbilt Lung Cancer Study (BioVU) is a case-control study nested within the Vanderbilt University Medical Center biobank, BioVU. BioVU is a biorepository of DNA extracted from blood drawn from patients seeking routine clinical care at Vanderbilt University Medical Center and linked to de-identified electronic health records for research purposes. Lung cancer cases and controls were identified from BioVU participants in February 2014. Lung cancer cases were identified from the Vanderbilt tumor registry. All specimens undergo pathologic review for determination of morphology. Coding of histology was based on SEER Program Coding Guidelines. Controls were randomly selected from BioVU participants, excluding cancer patients, and were matched to cases on age (± 5 years), sex, and race. Relevant covariates were identified from electronic health records using natural language processing. Genomic DNA was extracted based on a standard protocol.

Study phs001273

CIDR Estrogen Receptor Negative Breast Cancer in African American Women: DNA Methylation, Reproductive Events, and Mammary Epithelial Cell Populations

We conducted methylation profiling of breast tumor DNA from Formalin-Fixed Paraffin-Embedded (FFPE) samples for 1,550 cases from a cohort of Black women from the Black Women’s Health Study (BWHS), the Women’s Circle of Health Study (WCHS), and from the Pathways Study using the Illumina MethylationEPIC array. We will examine differentially methylated loci (DML) between ER+ and ER- tumors, and by age at onset of breast cancer. Combining these data with previously analyzed samples (n=385), we will consider associations between reproductive risk factors and top DML by age at diagnosis and ER status, examining the complex relationships between methylation, tumor and patient characteristics, and reproductive risk factors using structural equation modeling.

Study phs002688

Molecular Signatures of DCIS to Invasive Progression for Basal-Like Breast Cancers: An Integrated Mouse Model and Human Tumor Study

We studied the genomic signatures of progression in breast ductal carcinoma in situ (DCIS) as it progresses towards triple negative invasive breast cancer (TNBC). Single cell RNA sequencing (scRNAseq) was performed on the C3Tag genetically engineered mouse model that forms human breast-like DCIS and TNBC. Bulk RNA sequencing was performed on RNA harvested from archival formalin-fixed, paraffin embedded (FFPE) pairs comprising of estrogen receptor (ER) positive (ER+) and negative (ER-) subsets of DCIS. 

Study phs002443

A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers

This is a phase I clinical trial testing the safety and efficacy of gene-engineered T cells expressing a T-cell receptor targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR T cells) in patients with metastatic HPV-16+ epithelial cancers. A total of 12 patients were treated. The maximum tested dose was tolerated. Side effects were most consistent with the expected toxicities of the lymphocyte-depleting conditioning regimen and high-dose aldesleukin. Six of the 12 patients demonstrated objective clinical responses. Translational studies of the infused T cell characteristics did not correlate strongly with clinical response. Genomic defects in the targeted peptide-HLA complex did demonstrate definitive mechanisms of resistance in some patients.

Study phs002286

Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity

Targeted genetic sequencing was performed on a 41-year-old female with metaplastic breast cancer (MBC) and neurofibromatosis type I (NF1). A custom panel capturing 279 cancer related genes was used to identify a germline pathogenic SNV in NF1, as well several other somatic alterations.

Study phs001566

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

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