Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population
Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population
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DOI：
10.1038/s41391-018-0114-1
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发表时间：
2019-09-01
影响因子：
4.8
通讯作者：
Dean, Michael
中科院分区：
文献类型：
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作者：
Petrovics, Gyorgy;Price, Douglas K.;Dean, Michael
背景资料：BRCA 2的生殖系突变与前列腺癌（PCa）的高风险有关，最近在转移性去势抵抗性PCa标本中报告了BRCA 1和BRCA 2（BRCA 1/2）基因改变的高频率。BRCA 2基因突变在不同种族和民族中存在差异，包括非洲裔美国人（AA）和高加索裔美国人（CA）。（Ion AmpliSeq靶向测序）在三个不同队列中的1240名PCa患者（包括30%的AA患者）的存档血液DNA标本中进行分析：局限性早期（T2）PCa（N = 935）;晚期PCa（50% T3-4）（N = 189）和转移性PCa（N = 116）。分析BRCA 1/2中已知和新突变的序列。进行统计分析，以确定协会的突变与临床pathologicalparameters.Results：BRCA 2突变与已知的致病注释是显着更普遍的男性与晚期和转移性前列腺癌（3.1%）相比，患者的器官局限性疾病（0.7%）。与美国白人相比，AA患者携带未知意义的BRCA 1/2变异（VUS）的频率更高（分别为4.6%和1.6%）。值得注意的是，致病性BRCA 2基因突变的男性与本地化的早期PCa增加的风险，远处metastasis.Conclusions：生殖系变异的BRCA 1/2的意义不明更频繁的AA比CA PCa患者，然而，致病性突变的患病率是相似的跨种族。携带BRCA 2致病性突变的患者更有可能进展为转移。
Background: Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations.Methods: BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3-4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinicopathological parameters.Results: BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis.Conclusions: Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.