Human Molecular Genetics Advance Access originally published online on May 21, 2007
Human Molecular Genetics 2007 16(15):1794-1801; doi:10.1093/hmg/ddm127
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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 First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, 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 and Epidemiological Studies Unit (CTSU), University of Oxford, UK and 14 School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA
* To whom correspondence should be addressed at: Genetic Epidemiology Group, International Agency for Research on Cancer, 150 cours Albert Thomas, F 69372 Lyon Cedex 08, France. Tel: +33 472738391; Fax: +33 472738342; Email: brennan{at}iarc.fr
Received January 25, 2007; Accepted May 4, 2007
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. Four thousand and fifteen 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. The heterozygous (T/C) genotype was associated with a highly significantly lower incidence of lung cancer than the common T/T genotype [relative risk (RR), T/C versus T/T, 0.44, with 95% confidence interval (CI) 0.31–0.63, P < 0.00001] and with a significantly lower incidence 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). 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 squamous stem cell apoptosis following smoke exposure causes net harm (e.g. 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.
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