Brennan Paul, McKay James, Moore Lee, Zaridze David, Mukeria Anush, Szeszenia-Dabrowska Neonilia, Lissowska Jolanta, Rudnai Peter, Fabianova Eleonora, Mates Dana, Bencko Vladimir, Foretova Lenka, Janout Vladimir, Chow Wong-Ho, Rothman Nathanial, Chabrier Amelie, Gaborieau Valerie, Odefrey Fabrice, Southey Melissa, Hashibe Mia, Hall Janet, Boffetta Paolo, Peto Julian, Peto Richard, Hung Rayjean J
International Agency for Research on Cancer (IARC), Lyon, France.
Hum Mol Genet. 2007 Aug 1;16(15):1794-801. doi: 10.1093/hmg/ddm127. Epub 2007 May 21.
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.
CHEK2是一个关键的细胞周期控制基因，编码一种多能激酶，该激酶可因未修复的DNA损伤而导致细胞停滞或凋亡。我们报告了一项针对一种无功能变异体的大型病例对照研究，此前预计该变异体会增加癌症发病率。对中欧的4015名癌症患者（2250例肺癌、811例鳞状上呼吸道和消化道癌以及954例肾癌）和3052名对照者进行了错义变异体rs17879961（T被C取代）的基因分型，该变异改变了基因产物活性位点的一个氨基酸（I157T）。杂合子（T/C）基因型与肺癌发病率显著低于常见的T/T基因型相关[相对风险（RR），T/C与T/T相比，为0.44，95%置信区间（CI）为0.31 - 0.63，P < 0.00001]，并且与上呼吸道和消化道癌症发病率显著降低相关（RR 0.44，CI 0.26 - 0.73，P = 0.001；肺癌或上呼吸道和消化道癌症合并的P = 0.000001）。鳞状肺癌的保护作用显著大于腺癌（P = 0.001）。肾癌有边缘性显著增加（RR 1.44，CI 0.99 - 2.00，P = 0.06）。这种与烟草相关癌症发病率意外减半的情况（因为已独立重复验证）意味着吸烟者的绝对风险降低幅度比非吸烟者大得多。其机制尚不清楚：也许烟雾暴露后鳞状干细胞凋亡会造成净损害（例如，迫使附近的干细胞在修复自身因烟草烟雾造成的DNA损伤之前就进行分裂）。如果是这样，通过降低CHEK2活性来降低凋亡率可能具有保护作用——尽管不吸烟的保护作用要大得多。
