title: Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population.
abstract: The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD 20852, USA. liw9@mail.nih.gov
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Le-Min
authors.initials: LM
authors.lastname: Wang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.forename: Ti
authors.initials: T
authors.lastname: Ding
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Qiao
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Fan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Shi
authors.forename: Fangyi
authors.initials: F
authors.lastname: Gu
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Xiong
authors.forename: Carol
authors.initials: C
authors.lastname: Giffen
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D004260:DNA Repair; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C066780:Clk dual-specificity kinases; D064447:Checkpoint Kinase 2; D011505:Protein-Tyrosine Kinases; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases