Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers:: case-control study
Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers:: case-control study
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DOI：
10.1093/hmg/ddm127
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Hung, Rayjean J.
中科院分区：
文献类型：
--
作者：
Brennan, Paul;Mckay, James;Hung, Rayjean J.
CHEK 2是编码多能激酶的关键细胞周期控制基因，所述多能激酶可响应于未修复的DNA损伤而引起停滞或凋亡。我们报告了一个大型的病例对照研究的非功能性变异，以前预计会增加癌症发病率。4015例癌症患者（2250例肺癌，811例鳞状上呼吸消化道和954例肾癌）和3052例中欧对照者进行了错义变体rs 17879961（T被C取代）的基因分型，该变体改变了基因产物活性位点的氨基酸（I157 T）。杂合（T/C）基因型与肺癌发病率显著低于普通T/T基因型[相对危险度（RR），T/C vs. T/T，0.44，95%可信区间（CI）0.31-0.63，P < 0.00001]，与上呼吸消化道癌发病率显著降低相关（RR 0.44，CI 0.26-0.73，P = 0.001;肺癌或上呼吸消化道癌P = 0.000001）。鳞状细胞癌的保护作用明显大于腺瘤性肺癌（P = 0.001）。肾癌组的RR值高于正常对照组（RR 1.44，CI 0.99-2.00，P = 0.06）。这种与烟草有关的癌症的意外减半（因为独立复制）意味着吸烟者的绝对风险降低比非吸烟者大得多。机制不明：也许吸烟后鳞状干细胞凋亡会造成净伤害（例如，通过迫使附近的干细胞在修复烟草烟雾对其自身的DNA损伤之前进行分裂）。如果是这样的话，通过降低CHEK 2活性来降低细胞凋亡率可能是有保护作用的，尽管不吸烟的保护作用更大。
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, Cl 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.