Mutations in CHEK2 associated with prostate cancer risk
Mutations in CHEK2 associated with prostate cancer risk
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DOI：
10.1086/346094
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发表时间：
2003-02-01
影响因子：
9.8
通讯作者：
Liu, WG
中科院分区：
文献类型：
--
作者：
Dong, XY;Wang, L;Liu, WG
DNA损伤信号通路与所有人类癌症有关。然而，该通路在前列腺癌发生中的遗传缺陷和机制仍然知之甚少。在这项研究中，我们分析了CHEK 2，在DNA损伤信号通路中的p53的上游调节，在几组前列腺癌患者。在578例患者中共发现28例（4.8%）生殖系CHEK2突变（其中16例是独特的）。在149个家族性前列腺癌家族中对CHEK2突变进行的额外筛查显示，9个家族中有11个突变（5个独特）。这些突变包括两个移码突变和三个错义突变。重要的是，在423名未受影响的男性中，在散发性和家族性病例中鉴定的18种独特CHEK 2突变中有16种未检测到，表明CHEK 2突变在前列腺癌发展中的病理作用。使用逆转录酶聚合酶链反应和蛋白质印迹分析Epstein巴尔病毒转化的细胞系中的两个移码突变，揭示了一个突变的异常剪接和两种情况下CHEK 2蛋白水平的显著降低。总的来说，我们的数据表明CHEK2突变可能导致前列腺癌的风险，DNA损伤信号通路可能在前列腺癌的发展中发挥重要作用。
The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.