TY - JOUR
T1 - Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers
T2 - Case - Control study
AU - Brennan, Paul
AU - McKay, James
AU - Moore, Lee
AU - Zaridze, David
AU - Mukeria, Anush
AU - Szeszenia-Dabrowska, Neonilia
AU - Lissowska, Jolanta
AU - Rudnai, Peter
AU - Fabianova, Eleonora
AU - Mates, Dana
AU - Bencko, Vladimir
AU - Foretova, Lenka
AU - Janout, Vladimir
AU - Chow, Wong Ho
AU - Rothman, Nathanial
AU - Chabrier, Amelie
AU - Gaborieau, Valerie
AU - Odefrey, Fabrice
AU - Southey, Melissa
AU - Hashibe, Mia
AU - Hall, Janet
AU - Boffetta, Paolo
AU - Peto, Julian
AU - Peto, Richard
AU - Hung, Rayjean J.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34547851812&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddm127
DO - 10.1093/hmg/ddm127
M3 - Article
C2 - 17517688
AN - SCOPUS:34547851812
VL - 16
SP - 1794
EP - 1801
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 15
ER -