title: Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk.
abstract: Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1). Another SNP, which causes a nucleotide change in the 5'-UTR of MTH1 transcripts leading to alternative translation initiation, was additionally examined and the SNP also showed a significant association (OR=1.7, 95% CI: 1.2-2.3, P=0.002). The two SNPs in the MTH1 gene were in linkage disequilibrium, and the OR for carrying a copy of the haplotype consisting of both the risky SNP alleles was 2.0 (95% CI: 1.2-3.2, P=0.002). The present results indicate that inter-individual differences in MTH1 activities due to SNPs are involved in susceptibility to SCLC.
authors.affiliation: Center for Medical Genomics, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Tokuki
authors.initials: T
authors.lastname: Sakiyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nishiwaki
authors.forename: Daizo
authors.initials: D
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirose
authors.forename: Takashi
authors.initials: T
authors.lastname: Eguchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanagitani
authors.forename: Ryusei
authors.initials: R
authors.lastname: Saito
authors.forename: Rumie
authors.initials: R
authors.lastname: Sasaki-Matsumura
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mimaki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Toyama
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Sobue
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ohta
authors.forename: Misao
authors.initials: M
authors.lastname: Ohki
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D018288:Carcinoma, Small Cell / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D045643:DNA Repair Enzymes / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects
chemical_list: D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes