对 5545 名患有侵袭性和非侵袭性前列腺癌的男性进行种系 DNA 修复基因测序。
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.
机构信息
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.
出版信息
J Natl Cancer Inst. 2021 May 4;113(5):616-625. doi: 10.1093/jnci/djaa132.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
背景
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。
方法
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。
结果
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）。
结论
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。
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