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Carcinogenesis Advance Access originally published online on June 14, 2006
Carcinogenesis 2006 27(12):2448-2454; doi:10.1093/carcin/bgl095
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commerical License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk

Takashi Kohno1,2,{dagger}, Tokuki Sakiyama1,{dagger}, Hideo Kunitoh3, Koichi Goto4, Yutaka Nishiwaki4, Daizo Saito5, Hiroshi Hirose6,7, Takashi Eguchi7, Noriko Yanagitani8, Ryusei Saito8, Rumie Sasaki-Matsumura2, Sachiyo Mimaki1, Kaoru Toyama2, Seiichiro Yamamoto9, Aya Kuchiba9,10, Tomotaka Sobue9, Tsutomu Ohta1, Misao Ohki1 and Jun Yokota1,2,*

1 Center for Medical Genomics Tokyo
2 Biology Division, National Cancer Center Research Institute Tokyo
3 Division of Thoracic Oncology Tokyo
5 Department of Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital Tokyo
4 Division of Thoracic Oncology, National Cancer Center Hospital East Chiba
6 Health Center, Keio University School of Medicine Tokyo
7 Department of Internal Medicine, Keio University School of Medicine Tokyo
8 First Department of Internal Medicine, Gunma University School of Medicine Gunma
9 Statistics and Cancer Control Division, Research Center for Cancer Prevention and Screening, National Cancer Center Tokyo
10 Department of Biostatistics/Epidemiology and Preventive Health Sciences, Graduate School of Medicine, The University of Tokyo Tokyo, Japan

*To whom correspondence should be addressed. Tel: +81 3 3547 5272; Fax: +81 3 3542 0807; Email: jyokota{at}gan2.ncc.go.jp

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 (mutT 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.


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