Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study
Year: 2011
Type: article
Study design: Observational Study
Abstract: The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10(-5)) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer.
Source: Cancer Research
Authors: Shuguang Leng, Christine A. Stidley, Yushi Liu, Christopher K. Edlund, Randall P. Willink, Younghun Han, Maria Teresa Landi, Michael Thun, Maria A. Picchi, Shannon E. Bruse, Richard E. Crowell, David Van Den Berg, Neil E. Caporaso, Christopher I. Amos, Jill M. Siegfried, Yohannes Tesfaigzi, Frank D. Gilliland, Steven A. Belinsky
Institutions: University of Southern California, American Cancer Society, Lovelace Respiratory Research Institute, The University of Texas MD Anderson Cancer Center, University of New Mexico, University of Pittsburgh, National Cancer Institute, New Mexico VA Health Care System, Division of Cancer Epidemiology and Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: PROSTATE, LUNG, COLORECTAL &OVARIAN (PLCO) CANCER, G1129713815, PROSTATE, LUNG, COLORECTAL AND OVARIAN CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G1267016694, G1285883624, G142049768, Factors for Epigenetic Silencing of Lung Cancer Genes, G1578565442, PROSTATE, LUNG, COLORECTAL, AND OVARIAN (PLCO) CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G2070044820, G2250436683, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, SPORE in Lung Cancer, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, PROSTATE, LUNG, COLORECTAL, &OVARIAN CANCER SCREENING, PROSTATE, LUNG, COLORECTAL &OVARIAN CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN CANCER, G3166288362, G3446191057, G3986927127, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, Transdisciplinary Research in Cancer of the Lung (TRICL), G4922896994, G5198629111, G6219625355, G6375054419, G668214460, High Density Association Analysis of Lung Cancer, G7400349024, G7421337856, G7442572985, G8312728332, G840131496, G8509316824, G957887912, G979407967, G996329585
OpenAlex ID: W2171347021