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Carcinogenesis Advance Access originally published online on February 14, 2008
Carcinogenesis 2008 29(4):762-765; doi:10.1093/carcin/bgn044
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers

Cezary Cybulski*, Bartlomiej Masojc, Dorota Oszutowska, Ewa Jaworowska1, Tomasz Grodzki2, Piotr Waloszczyk2, Piotr Serwatowski2, Juliusz Pankowski2, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Anna Jakubowska, Tadeusz Debniak, Dominika Wokolorczyk, Jacek Gronwald, Czeslawa Tarnowska1, Pablo Serrano-Fernández, Jan Lubinski and Steven A. Narod3

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, ul. Polabska 4, 70-115 Szczecin, Poland
1 Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, ul.Unii Lubelskiej, 71–252 Szczecin, Poland
2 Lung Diseases Hospital, ul. Sokolowskiego 11, 70–891 Szczecin, Poland
3 Women's College Research Institute, Toronto, Ontario M5G IN8, Canada

* To whom correspondence should be addressed. Tel: +48 91 466 1532; Fax: +48 91 466 1533; Email: cezarycy{at}sci.pam.szczecin.pl

Mutations in the CHEK2 gene have been associated with increased risks of breast, prostate and colon cancer. In contrast, a previous report suggests that individuals with the I157T missense variant of the CHEK2 gene might be at decreased risk of lung cancer and upper aero-digestive cancers. To confirm this hypothesis, we genotyped 895 cases of lung cancer, 430 cases of laryngeal cancer and 6391 controls from Poland for four founder alleles in the CHEK2 gene, each of which has been associated with an increased risk of cancer at several sites. The presence of a CHEK2 mutation was protective against both lung cancer [odds ratio (OR) = 0.3; 95% confidence interval (CI) 0.2–0.5; P = 3 x 10–8] and laryngeal cancer (OR = 0.6; 95% CI 0.3–0.99; P = 0.05). The basis of the protective effect is unknown, but may relate to the reduced viability of lung cancer cells with a CHEK2 mutation. Lung cancers frequently possess other defects in genes in the DNA damage response pathway (e.g. p53 mutations) and have a high level of genotoxic DNA damage induced by tobacco smoke. We speculate that lung cancer cells with impaired CHEK2 function undergo increased rates of cell death.

Abbreviations: CI, confidence interval; OR, odds ratio; PCR, polymerase chain reaction

Received December 18, 2007; revised December 18, 2007; accepted February 2, 2008.


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