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.