Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Eur Urol. 2020 Jan;77(1):24-35. doi: 10.1016/j.eururo.2019.08.025. Epub 2019 Sep 6.
BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.
To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.
DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).
Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.
Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.
The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.
In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.
BRCA1 和 BRCA2 突变与前列腺癌（PCa）风险相关，但基于回顾性研究的风险估计范围广泛。
评估与 BRCA1/2 突变相关的相对和绝对 PCa 风险，并评估年龄、家族史和突变位置对风险的影响。
设计、设置和参与者：这是一项前瞻性队列研究，纳入了在英国和爱尔兰的临床遗传学中心确定的男性 BRCA1（n=376）和 BRCA2 携带者（n=447）（中位随访时间分别为 5.9 年和 5.3 年）。
使用队列和生存分析方法，根据人群发病率或死亡率，估计标准化发病率/死亡率比（SIRs/SMRs）、绝对风险和风险比（HRs）。
在随访期间，16 名 BRCA1 携带者和 26 名 BRCA2 携带者被诊断为 PCa。BRCA2 携带者的 SIR 为 4.45（95%置信区间 [CI] 2.99-6.61），绝对 PCa 风险分别为 27%（95%CI 17-41%）和 60%（95%CI 43-78%），分别在 75 和 85 岁时达到。对于 BRCA1 携带者，总 SIR 为 2.35（95%CI 1.43-3.88）；年龄<65 岁时的相应 SIR 为 3.57（95%CI 1.68-7.58）。然而，在评估潜在筛查效果的敏感性分析中，BRCA1 的 SIR 在 0.74 至 2.83 之间变化。BRCA2 携带者的 PCa 风险随着家族史而增加（每有一个受累亲属的 HR 为 1.68，95%CI 0.99-2.85）。与人群发病率相比，位于位置 c.2831 和 c.6401 之间的 BRCA2 突变的 SIR 为 2.46（95%CI 1.07-5.64），对应于较低的 PCa 风险（HR 0.37，95%CI 0.14-0.96），低于该区域外的突变。BRCA2 携带者与 Gleason 评分≥7 的 PCa（SIR 5.07，95%CI 3.20-8.02）的相关性强于 Gleason 评分≤6 的 PCa（SIR 3.03，95%CI 1.24-7.44），且 PCa 死亡率更高（SMR 3.85，95%CI 1.44-10.3）。局限性包括这些已知突变携带者的潜在筛查效果；然而，BRCA2 的结果在多项敏感性分析中是稳健的。
这些结果证实了 BRCA2 携带者的回顾性分析所示的 PCa 风险模式，包括与侵袭性 PCa 进一步相关的证据，并为 BRCA1 携带者的相关性较弱提供了一些支持。
在这项研究中，我们随访了已知携带 BRCA1 和 BRCA2 基因突变的未患病男性，以调查他们与一般人群相比是否有更高的患前列腺癌风险。我们发现，BRCA2 突变携带者患前列腺癌的风险很高，特别是更具侵袭性的前列腺癌，并且这种风险因家族史和基因突变在基因中的位置而异。
