Human Molecular Genetics Advance Access published online on May 21, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm127
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case-control study
1 International Agency for Research on Cancer (IARC), Lyon, France 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Bethesda, MD, USA 3 Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia 4 Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland 5 Department of Epidemiology and Cancer Prevention, Maria Sklodowska Institute of Oncology, Warsaw, Poland 6 Johan National Institute of Public Health, Budapest, Hungary 7 Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia 8 Institute of Public Health, Bucharest, Romania 9 Charles University in Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Czech Republic 10 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic 11 Department of Preventive Medicine, Palacky University of Medicine, Olomouc, Czech Republic 12 London School of Hygiene and Tropical Medicine, University of London, UK 13 Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), University of Oxford, UK 14 School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA
* Correspondence to: Paul Brennan, Genetic Epidemiology Group, International Agency for Research on Cancer, 150 cours Albert Thomas, F 69372 Lyon Cedex 08, France brennan{at}iarc.fr Tel: +33 472738391, Fax: +33 472738342
Received January 25, 2007; Revised May 4, 2007; Accepted May 4, 2007
Background: CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage. We report a large case-control study of a non-functional variant that had previously been expected to increase cancer rates.
Methods: 4015 cancer patients (2250 lung, 811 squamous upper aero-digestive and 954 kidney) and 3052 controls in central Europe were genotyped for the mis-sense variant rs17879961 (replacement of T by C), which changes an amino-acid (I157T) in an active site of the gene product.
Findings: The heterozygous (T/C) genotype was associated with a highly significantly lower incidence of lung cancer than the common T/T genotype (relative risk, T/C versus T/T, [RR] 0·44, with 95% confidence interval [CI] 0·31-0·63, p<0·00001) and with a significantly lowerincidence of upper aero-digestive cancer (RR 0·44, CI 0·26-0·73, p=0·001; p=0.000001 for lung or upper aero-digestive cancer). Protection was significantly greater for squamous than adenomatous lung cancer (p=0·001). There was an increase of borderline significance in kidney cancer (RR 1·44, CI 0·99-2·00, p=0·06).
Interpretation: This unexpected halving of tobacco-related cancer (since replicated independently) implies much greater absolute risk reduction in smokers than in non-smokers. The mechanism is unknown: perhaps stem cell apoptosis following smoke exposure causes net harm (eg, by forcing nearby stem cells to divide before they have repaired their own DNA damage from tobacco smoke). If so, reducing the rate of apoptosis by reducing CHEK2 activity could be protective - although not smoking would be far more so.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C Cybulski, B Gorski, T Huzarski, T Byrski, J Gronwald, T Debniak, D Wokolorczyk, A Jakubowska, P Serrano-Fernandez, T Dork, et al. Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations J. Med. Genet., February 1, 2009; 46(2): 132 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bethke, K. Sullivan, E. Webb, A. Murray, M. Schoemaker, A. Auvinen, A. Kiuru, T. Salminen, C. Johansen, H. C. Christensen, et al. The Common D302H Variant of CASP8 Is Associated with Risk of Glioma Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 987 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cybulski, B. Masojc, D. Oszutowska, E. Jaworowska, T. Grodzki, P. Waloszczyk, P. Serwatowski, J. Pankowski, T. Huzarski, T. Byrski, et al. Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers Carcinogenesis, April 1, 2008; 29(4): 762 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Hung, M. Baragatti, D. Thomas, J. McKay, N. Szeszenia-Dabrowska, D. Zaridze, J. Lissowska, P. Rudnai, E. Fabianova, D. Mates, et al. Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2736 - 2744. [Abstract] [Full Text] [PDF]
|
|