Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
The Institute of Cancer Research, London, UK.
J Natl Cancer Inst. 2021 May 4;113(5):616-625. doi: 10.1093/jnci/djaa132.
There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.
Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.
BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).
Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
迫切需要确定与侵袭性前列腺癌（PCa）风险特别相关的因素。我们通过侵袭性疾病与非侵袭性疾病的病例对照研究，调查了 DNA 修复基因中罕见的致病性、可能致病性或有害（P/LP/D）种系变异是否与侵袭性 PCa 风险相关。
参与者为 5545 名欧洲血统男性，包括 2775 名非侵袭性和 2770 名侵袭性 PCa 病例，其中 467 例为转移性病例（16.9%）。样本来自 12 项国际研究，一起进行种系测序。对 155 个 DNA 修复基因进行罕见（次要等位基因频率<0.01）的 P/LP/D 变体分析。我们比较了基于疾病侵袭性的单变异、基于基因和基于 DNA 修复途径的负担。所有统计检验均为双侧。
BRCA2 和 PALB2 的基因相关性最显著，2.5%的侵袭性病例和 0.8%的非侵袭性病例携带 P/LP/D BRCA2 等位基因（比值比[OR] = 3.19，95%置信区间[CI] = 1.94 至 5.25，P = 8.58×10-7），而 0.65%的侵袭性病例和 0.11%的非侵袭性病例携带 P/LP/D PALB2 等位基因（OR = 6.31，95%CI = 1.83 至 21.68，P = 4.79×10-4）。ATM 存在名义关联，1.6%的侵袭性病例和 0.8%的非侵袭性病例携带 P/LP/D ATM 等位基因（OR = 1.88，95%CI = 1.10 至 3.22，P =.02）。总的来说，在 24 个经文献证实的候选 PCa DNA 修复基因中，侵袭性病例中 P/LP/D 等位基因更为常见（携带频率分别为 14.2%和 10.6%；P = 5.56×10-5）。然而，在排除 BRCA2、PALB2 和 ATM 后，这种差异无统计学意义（P =.18）。在这 24 个基因中，P/LP/D 携带者的诊断年龄平均年轻 1.06 岁（95%CI=-1.65 至 0.48，P = 3.71×10-4）。
DNA 修复基因的风险主要由 BRCA2、PALB2 和 ATM 内的罕见 P/LP/D 等位基因驱动。这些发现支持这些基因在筛查和疾病管理方面的重要性。
