Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Cancer Med. 2022 Nov;11(22):4332-4340. doi: 10.1002/cam4.4778. Epub 2022 Apr 25.
Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low-risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance.
Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively.
Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2. The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36-2.06, p = 0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%).
The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.
几种罕见的外显率高的致癌基因突变与侵袭性前列腺癌（PC）风险增加相关。我们的目的是确定在主动监测中低危 PC 男性患者中致病性种系突变的发生率，并评估在初始监测后接受治疗的男性中，致病性种系突变是否与分级重新分类或不良病理、复发或转移相关。
前瞻性纳入 Canary 前列腺主动监测研究（PASS）的男性患者进行了回顾性抽样研究。利用遗传性癌症基因谱对种系 DNA 进行测序。根据美国临床遗传学会和基因组学指南对突变进行分类。通过加权 Cox 比例风险模型和条件逻辑回归分别评估致病性种系突变与分级重新分类和不良特征的相关性。
总体而言，437 名研究参与者中有 29 名（6.6%）携带致病性种系突变，其中 19 名发生在参与 DNA 修复的基因中（4.3%）。8 名患者（1.8%）在三个与侵袭性 PC 相关的基因中携带致病性种系突变：ATM、BRCA1 和 BRCA2。DNA 修复基因中致病性种系突变的存在与不良特征无关（单因素分析 HR=0.87，95%CI：0.36-2.06，p=0.7）。ATM、BRCA1 和 BRCA2 中致病性种系突变的携带者率在分级重新分类或无分级重新分类的男性中没有差异（1.9%与 1.8%）。
在接受主动监测的 PC 男性中，外显率高的致癌基因突变的发生率极低，致病性种系突变与分级重新分类或不良特征无明显相关性。
