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.]]>
PLCO Baseline Questionnaire For Male Participants (BQM3)PLCO Baseline Questionnaire For Female Participants (BQF3)PLCO Baseline Questionnaire -- Variables available as of July 14, 2005Bibliography of Journal Articles from PLCOBiospecimen Resources in PLCOCancer Screening in PLCOCollection of Biospecimens in PLCOEndpoint Assessment in PLCOPLCO Consent For ParticipationDesign and Evolution of the Data Management Systems in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening TrialPLCO Medical Record Abstract Form Treatment Information - Lung (TIL2/TLQ2)PLCO Medical Record Abstract Form Diagnostic Evaluation - Lung (DEL3/DLQ3)Coordination and Management of a Large Multicenter Screening Trial: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening TrialDesign of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening TrialQuestionnaires and Other Data Collection Forms in PLCORecruiting Participants and Determining Eligibility in PLCOStorage of Biospecimens in PLCOEAGLE Form 05A – Blood drawing, CasesEAGLE Form 05B – Tracking Blood Sample– CasesEAGLE Form 06 – DiagnosisEAGLE Form 07 – Case ChecklistEAGLE Form 21 – Blood drawing and transport, Controls and SibsEAGLE Biospecimen Collection ProtocolsEAGLE CAPI QUESTIONNAIREEAGLE Database DescriptionEAGLE Study ManagementDescription of EAGLE Database AND Definition of some EAGLE Derived VariablesEAGLE Consent to participate for CASESEAGLE Consent to participate for CONTROLSEAGLE Standard Operating ProceduresEAGLE GELCS –QUALITY CONTROL PROCEDURESEAGLE Proposed CodingEAGLE SELF-ADMINISTERED QUESTIONNAIREEAGLE Case ascertainment Cases were identified through a group of hospitals which include catchment of greater than 80% of the lung cancer cases in a defined geographic area in the Lombardy region of Italy including Milan, with a first diagnosis of lung cancer between April 22, 2002 and February 28, 2005. The case group consisted of ~2,000 newly incident lung cancer cases, born in Italy, of Italian nationality, with official residence in one of 216 selected municipalities, male and female, 35 to 79 years old, collected before or after surgery and prior to chemotherapy or radiation therapy. All histologic types and stages of lung cancer are represented. Cases were consecutively collected in the departments of thoracic surgery, general surgery, general medicine, and oncology of the participating hospitals. Subjects in intensive care units, or with cardiac, hepatic, renal, or CNS failure, or with uncompensated schizophrenia, psychosis, or inability to speak were excluded. Control ascertainment The control group consisted of ~2,000 gender and age- and region- matched subjects selected through the Regional Health Services Database. Other exclusion criteria are the same as for the case group. All study participants provided written informed consent. PLCO PLCO is a randomized screening study with a cohort design. Patients are stratified by participating center, gender, and age (55-59 vs 60-64 vs 65-69 vs 70-74) and randomized to one of two treatment arms. In the Control arm, patients receive standard medical care. In the Screened arm, all patients undergo sigmoidoscopic examination and chest x-ray; men also undergo DRE (Digital rectal exam) and PSA (Prostate-specific antigen) testing and women undergo a transvaginal ultrasound and CA-125 (Cancer Antigen-125) test. A scheduling and tracking procedure is implemented to ensure regular attendance at repeat screens for subjects screened negative or for those who are designated suspicious or positive at screening but for whom subsequent diagnostic procedures do not reveal prostate, lung, colorectal, or ovarian cancer (follow-up diagnostic procedures are through their own medical care environment). Patients diagnosed via a screening test with cancer of the prostate, lung, colorectum, or ovary are referred for treatment in accordance with current accepted practice for appropriate stage of disease, patient age, and medical condition; DRE (men only), transvaginal ultrasound (women only), and chest x-ray are repeated annually for 3 years. Patients who have never smoked do not receive a third chest x-ray. A Periodic Survey of Health questionnaire is mailed to each participant annually for 13 years to identify all prevalent and incident cancers of the prostate, lung, colorectum, and ovary as well as all deaths that occur among both screened and control subjects during the trial. ]]>
EAGLE EAGLE is a large population-based case-control study designed and conducted to investigate the genetic and environmental determinants of lung cancer and smoking persistence using an integrative approach that allows combined analysis of genetic, environmental, clinical, and behavioral data. The study includes over 2,000 incident lung cancer cases, both males and females of Italian nationality, ages 35 to 79 years old, with verified lung cancer of any histological type, and over 2,000 healthy population-based controls matched to cases by age, gender, and residence. The participation rate was high: 85% and 73% in cases and controls, respectively. Lung cancer cases were enrolled from 13 hospitals within the Lombardy region of Italy. The healthy controls were randomly selected from the same residential area of the lung cancer cases. The study setting, the Lombardy region of Italy, is served by a network of modern hospitals, medical schools, and a regional health service. Within the Lombardy region, the catchment's area includes 5 cities and 216 surrounding municipalities, encompassing, in the selected age range, over 1.3 million people. Extensive epidemiological data have been collected through both an interview-based computer-assisted questionnaire and a self-administered questionnaire. Available data includes demographical characteristics, detailed smoking history (active and passive), family history of lung cancer and other cancers, previous lung diseases, medications, diet, alcohol, attempts at quitting smoking, anxiety, depression, personality scores, occupation, reproductive and residential history. Clinical data (stage, grade, histology, imaging and pathology reports, spirometry, and routine laboratory studies) were recorded. All study subjects donated a blood sample (or, rarely, a buccal rinse sample), which was processed to obtain cryopreserved lymphocytes, RBC, granulocytes, DNA, RNA, whole blood, buffy coat, serum, plasma, and blood cards. Lung tissue paraffin blocks and slides were collected from the cases who underwent surgery, biopsy or cytological examination of the lung tumor. Multiple fresh "normal" lung tissue and tumor samples, frozen in liquid nitrogen within 20 minutes of excision, were also collected from over 500 surgical cases. All data and biospecimen information are stored in a secure relational database. Quality control procedures were implemented to ensure accuracy, completeness, and privacy of the data collected. Genetic and epidemiological studies are ongoing. This study will help answer many questions related to lung cancer etiology in the near future. PLCO The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a multi-center clinical trial sponsored by the National Cancer Institute. The purpose of the PLCO Trial is to determine whether certain cancer screening tests reduce deaths from these cancers of the prostate, lung, colorectum, and ovaries. Together, these four cancers account for about 60% of all diagnosed cancers in the United States. Enrollment opened in 1993 and ended in 2001, with over 155,000 men and women participating at 10 locations throughout the United States. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Data were scanned into on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and there is an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences.]]>