Reviews Department, Kleijnen Systematic Reviews Ltd., Escrick, York YO19 6FD, UK.
Information Department, Kleijnen Systematic Reviews Ltd., Escrick, York YO19 6FD, UK.
Int J Oncol. 2019 Sep;55(3):597-616. doi: 10.3892/ijo.2019.4842. Epub 2019 Jul 16.
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.
目前正在进行的几项国际性前列腺癌（PC）临床研究探索了靶向 DNA 损伤反应（DDR）通路的治疗方法。本系统综述总结了在未选择（一般）PC 和家族性 PC 人群中 DDR 突变携带者的流行率。从研究开始到 2017 年 12 月，共检索了 11 个电子数据库、10 个会议记录和灰色文献来源。总结了报告体细胞和/或种系 DDR 突变流行率的研究。包括转移性 PC（mPC）、去势抵抗性 PC（CRPC）和转移性 CRPC（mCRPC）亚组。共检索到 11648 条记录，纳入了所有 PC 人群的 80 项研究（103 条记录）；59 条记录为未选择的 PC，13 条记录为家族性 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 伴侣和定位器（PALB2）的突变率最高（≥4%）。种系 DDR 基因突变的中位流行率为 PC 中 18.6%（范围为 17.2%至 19%；三项研究，n=1712）、mPC 中 11.6%（范围为 11.4%至 11.8%；两项研究，n=1261）和 mCRPC 中 8.3%（范围为 7.5%至 9.1%；两项研究，n=738）。PC 中体细胞 DDR 基因突变的中位流行率为 10.7%（范围为 4.9%至 22%；三项研究，n=680）、mPC 中 13.2%（范围为 10%至 16.4%；两项研究，n=105）和 mCRPC 中未报告（NR）。PC 中 DDR 种系和/或体细胞突变的流行率为 27%（一项研究，n=221）、mCRPC 中 22.67%（一项研究，n=150）和 mPC 中 NR。在家族性 PC 中，种系 DDR 的中位突变流行率为 12.1%（范围为 7.3%至 16.9%）（两项研究，n=315），BRCA2 的中位突变流行率为 3.7%（范围为 1.3%至 7.9%）（六项研究，n=945）。总的来说，88%的研究存在高偏倚风险。PC 中体细胞亚组中 DDR 基因突变的流行率差异很大，这取决于研究规模、遗传筛选技术、DDR 突变定义和 PC 诊断；PC 中体细胞和/或种系 DDR 突变的流行率在 23%-27%之间。这些发现支持对所有 PC 患者（包括 mCRPC 患者）进行 DDR 基因突变检测。随着最新的临床实践 PC 指南强调 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，未来需要进行更大规模的流行病学研究，以进一步量化 PC 中 DDR 突变的国际负担。
