DCEG investigators have coordinated multiple genome-wide association studies (GWAS) of lung cancer. Each of these efforts is described below:
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. Investigators are conducting a whole genome study of lung cancer and smoking to examine the contribution of common inherited variants to lung cancer risk and progression. 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 study design efficiently allows identification of genes that also contribute to smoking persistence and outcome from lung cancer. Investigators are conducting a single GWAS of 5,900 subjects using the primary GENEVA dataset, made up of participants from two studies: the Environment and Genetics in Lung Cancer Etiology Study (EAGLE) and the Prostate, Lung, Colon and Ovary Study (PLCO) Cancer Screening Trial. EAGLE is 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. PLCO contributed ~850 lung cancer cases and ~850 controls, also matched on age and gender.
The same GWAS data 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.
Three genetic loci for lung cancer risk have been identified by GWAS, but inherited susceptibility to specific histologic types is not well established. We conducted a GWAS of lung cancer and its major histologic types genotyping 515,922 single nucleotide polymorphisms (SNPs) in 5,739 incident lung cancer cases and 5,848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from 10 additional studies for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication resulting in 3,333 adenocarcinomas (AD), 2,589 squamous cell carcinomas (SQ), and 1,418 small cell carcinomas (SC).
Investigators conducted a two-stage GWAS to evaluate the association between common genetic variants and the risk of lung cancer in African Americans. The stage 1 included 1,737 cases and 3,602 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 & 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 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.
Investigators conducted a GWAS of lung cancer among never-smoking women in Asia to identify new genetic variants or genomic regions that may be important in lung cancer pathogenesis in never-smokers. International collaborations were developed to facilitate accrual of blood or buccal cell DNA on a large set of lung cancer cases. One such collaboration, the Female Lung Cancer Consortium in Asia (FLCCA), includes studies in Taiwan, Mainland China, South Korea, Japan, Hong Kong, and Singapore. Utilizing FLCCA, investigators analyzed a total of 5,510 lung cancer cases and 4,544 controls, and identified 3 novel loci (Lan et al., 2012). Of these study subjects, 4,922 lung cancer cases and 3,959 controls are available for posting.