TY - JOUR
T1 - Genetic determinants for promoter hypermethylation in the lungs of smokers
T2 - A candidate gene-based study
AU - Leng, Shuguang
AU - Stidley, Christine A.
AU - Liu, Yushi
AU - Edlund, Christopher K.
AU - Willink, Randall P.
AU - Han, Younghun
AU - Landi, Maria Teresa
AU - Thun, Michael
AU - Picchi, Maria A.
AU - Bruse, Shannon E.
AU - Crowell, Richard E.
AU - Van Den Berg, David
AU - Caporaso, Neil E.
AU - Amos, Christopher I.
AU - Siegfried, Jill M.
AU - Tesfaigzi, Yohannes
AU - Gilliland, Frank D.
AU - Belinsky, Steven A.
PY - 2012/2/1
Y1 - 2012/2/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84863011111&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-11-3194
DO - 10.1158/0008-5472.CAN-11-3194
M3 - Article
C2 - 22139380
AN - SCOPUS:84863011111
SN - 0008-5472
VL - 72
SP - 707
EP - 715
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -
