一些正在进行的国际前列腺癌(PC)临床试验正在探索靶向DNA损伤反应(DDR)途径的疗法。本系统综述总结了DDR突变携带者在未选择的(一般)PC和家族性PC人群中的患病率。共有11个电子数据库,10会议记录,和灰色文献来源从其开始至2017年12月进行搜索.总结了报告体细胞和/或种系DDR突变患病率的研究。转移性PC(mPC),包括去势抗性PC(CRPC)和转移性CRPC(mCRPC)亚组。共检索到11,648条记录,纳入了所有PC人群的80项研究(103条记录);59条记录是未选择的PC,13条记录是家族性PC.大多数数据可用于DDR面板(n=12项研究),共济失调毛细血管扩张突变(ATM;n=13),乳腺癌易感基因(BRCA)1(n=14)和BRCA2(n=20)。ATM,BRCA2和BRCA2的伴侣和定位器(PALB2)的突变率最高(≥4%)。在PC中,DDR种系突变的中位患病率为18.6%(范围,17.2-19%;三项研究,n=1,712),11.6%的mPC(范围,11.4-11.8%;两项研究,n=1,261)和8.3%的mCRPC(范围,7.5-9.1%;两项研究,n=738)。在PC中DDR体细胞突变的中位患病率为10.7%(范围,4.9-22%;三项研究,n=680),13.2%的mPC(范围,10-16.4%;两项研究,n=105),在mCRPC中未报告(NR)。在PC中,DDR种系和/或体细胞突变的患病率为27%(一项研究,n=221),mCRPC中22.67%(一项研究,n=150)和NR在mPC中。在家庭个人电脑中,中位突变患病率为12.1%(范围,7.3-16.9%)用于种系DDR(两项研究,n=315)和3.7%(范围,1.3-7.9%)用于BRCA2(六项研究,n=945)。总的来说,88%的研究存在高偏倚风险。根据研究规模的不同,在PC中DDR基因突变的患病率在体细胞亚组中差异很大。基因筛选技术,DDR突变定义和PC诊断;PC中的体细胞和/或种系DDR突变患病率在23-27%的范围内。这些发现支持对所有PC患者(包括mCRPC患者)进行DDR突变测试。随着最新临床实践PC指南的出现,突出了DDR突变筛查的重要性,以及正在进行的mCRPC临床试验评估DDR突变靶向药物,未来更大规模的流行病学研究有必要进一步量化PC中DDR突变的国际负担.
Several ongoing international prostate cancer (PC) clinical trials are exploring therapies that target the DNA damage response (DDR) pathway. This systematic
review summarizes the prevalence of DDR mutation carriers in the unselected (general) PC and familial PC populations. A total of 11 electronic databases, 10 conference proceedings, and grey literature sources were searched from their inception to December 2017. Studies reporting the prevalence of somatic and/or germline DDR mutations were summarized. Metastatic PC (mPC), castration‑resistant PC (CRPC) and metastatic CRPC (mCRPC) subgroups were included. A total of 11,648 records were retrieved, and 80 studies (103 records) across all PC populations were included; 59 records were of unselected PC and 13 records of familial PC. Most data were available for DDR panels (n=12 studies), ataxia telangiectasia mutated (ATM; n=13), breast cancer susceptibility gene (BRCA)1 (n=14) and BRCA2 (n=20). ATM, BRCA2 and partner and localizer of BRCA2 (PALB2) had the highest mutation rates (≥4%). Median prevalence rates for DDR germline mutations were 18.6% in PC (range, 17.2‑19%; three studies, n=1,712), 11.6% in mPC (range, 11.4‑11.8%; two studies, n=1,261) and 8.3% in mCRPC (range, 7.5‑9.1%; two studies, n=738). Median prevalence rates for DDR somatic mutations were 10.7% in PC (range, 4.9‑22%; three studies, n=680), 13.2% in mPC (range, 10‑16.4%; two studies, n=105) and not reported (NR) in mCRPC. The prevalence of DDR germline and/or somatic mutations was 27% in PC (one study, n=221), 22.67% in mCRPC (one study, n=150) and NR in mPC. In familial PC, median mutation prevalence was 12.1% (range, 7.3‑16.9%) for germline DDR (two studies, n=315) and 3.7% (range, 1.3‑7.9%) for BRCA2 (six studies, n=945). In total, 88% of studies were at a high risk of bias. The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23‑27% in PC. These findings support DDR mutation testing for all patients with PC (including those with mCRPC). With the advent of the latest clinical practice PC guidelines highlighting the importance of DDR mutation screening, and ongoing mCRPC clinical trials evaluating DDR mutation‑targeted drugs, future larger epidemiological studies are warranted to further quantify the international burden of DDR mutations in PC.