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Carcinogenesis Advance Access published online on February 14, 2008
Carcinogenesis, 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 Cybulski1, Bartlomiej Masojc1, Dorota Oszutowska1, Ewa Jaworowska2, Tomasz Grodzki3, Piotr Waloszczyk3, Piotr Serwatowski3, Juliusz Pankowski3, Tomasz Huzarski1, Tomasz Byrski1, Bohdan Górski1, Anna Jakubowska1, Tadeusz Debniak1, Dominika Wokolorczyk1, Jacek Gronwald1, Czeslawa Tarnowska2, Jan Lubinski1 and Steven A. Narod4

1 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
2 Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Szczecin, Poland
3 Lung Diseases Hospital, Szczecin, Poland
4 Women's College Research Institute, Toronto, Ontario, Canada

Address correspondence to: Cezary Cybulski, International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, ul. Polabska 4, 70-115 Szczecin. Tel: 00 48 91 466 1532, Fax: 00 48 91 466 1533, e-mail: 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 (OR = 0.3; 95% CI 0.2 to 0.5; p = 3 x 10-8) and laryngeal cancer (OR = 0.6; 95% CI 0.3 to 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.

Key Words: lung cancer • laryngeal cancer • CHEK2 • CHK2 • germline mutations

Received November 19, 2007; revised January 22, 2008; accepted January 28, 2008.


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