Clinical and Functional Analyses of p73R1 Mutations in Prostate Cancer

摘要

The DNA damage-signaling pathway has been implicated in the development of prostate cancer. Germline mutations in several genes (BRCA1, BRCA2, and CHEK2) whose products are involved in this pathway have been associated with increased risk for this disease. To identify additional genes in this pathway that might confer susceptibility to prostate cancer, we isolated a p73 up-regulated gene (p73R1) and screened this gene for mutations in prostate cancer. Two germline truncating mutations were identified. Genotyping of 403 men with sporadic prostate cancer for the two mutations showed a frequency of 3.2% (13/403) in contrast to 0.6% (2/327) in 327 population-based controls (Fisher's exact test, P=0.016), with an odds ratio of 5.4 (95% confidence interval 1.2-24.2). Analyses of 994 affected men from 444 familial prostate cancer families showed a relatively lower frequency of 1.6% but no mutations were found in 100 unaffected men from these families, indicating a similar trend observed for other comparisons. Overall, our data suggest that germline p73R1 truncating mutations may predispose men to prostate cancer and further supports the concept that the mutant alleles in the DNA damage-response genes play an important role in the development of sporadic prostate cancer.