CHK2, A Candidate Prostate Cancer Susceptibility Gene

摘要

The DNA damage-response pathway has been implicated in many human cancers and cancer-prone diseases. However, this area has been understudied in prostate cancer. In this study, we tested our hypothesis that genetic defects in this pathway may confer susceptibility to prostate cancer using a mutation screening of candidate gene approach. We screened for mutations in CHK2, a direct upstream regulator of p53, and identified a total of 28 (4.8%) germline CHK2 mutations in 178 primary prostate tumors, 149 familial prostate cancer families, and 400 sporadic cases. Sixteen of the 18 unique CRK2 mutations identified in this study were not detected among 423 unaffected men, suggesting that CHK2 mutations have increased risk of developing prostate cancer. We analyzed loss of heterozygosity (LOH) in 21 prostate tumors harboring CHK2 mutations and found 6 of them lost the wild-type alleles, suggesting that CHK2 is a tumor suppressor. By analysis of patients' EBV-transformed cell lines and by kinase activity assays of cell lines stably expressing the CHK2 mutants, we demonstrated that the mutant CHK2 reduced ability to response to DNA damage through either reduction of CHK2 protein level or reduction of CHK2 kinase activity. Collectively, our data provide evidence for the first time that the germline CHK2 mutations confer susceptibility to prostate cancer. Mutations in CHK2 may promote tumorigenesis in prostate through altering CHK2 expression level and/or kinase activity.