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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Leng S,Stidley CA,Liu Y,Edlund CK,Willink RP,Han Y,Landi MT,Thun M,Picchi MA,Bruse SE,Crowell RE,Van Den Berg D,Caporaso NE,Amos CI,Siegfried JM,Tesfaigzi Y,Gilliland FD,Belinsky SAdoi
10.1158/0008-5472.CAN-11-3194subject
Has Abstractpub_date
2012-02-01 00:00:00pages
707-15issue
3eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-11-3194journal_volume
72pub_type
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