Willems Amber J, Dawson Sarah-Jane, Samaratunga Hema, De Luca Alessandro, Antill Yoland C, Hopper John L, Thorne Heather J
Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Research Department, Peter MacCallum Cancer Centre, Victoria, Australia.
Clin Cancer Res. 2008 May 15;14(10):2953-61. doi: 10.1158/1078-0432.CCR-07-5237. Epub 2008 Apr 29.
Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors.
From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation; (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the family-specific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation; and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification of DNA from microdissected tumor.
LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1 was observed in four tumors from BRCA1 mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95% confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature.
These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.
携带BRCA2（可能还有BRCA1）致病种系突变的男性患前列腺癌的风险会增加。我们的主要目的是检测携带BRCA1或BRCA2致病种系突变的男性前列腺癌中突变位点的杂合性缺失（LOH），并评估这些肿瘤的临床和病理特征。
从1243个kConFab家族中：（a）215个家族携带BRCA1致病突变，188个家族携带BRCA2致病突变；（b）在158名被诊断为前列腺癌的男性（来自137个家族）中，8名被证实携带家族特异性BRCA1突变，20名被证实携带家族特异性BRCA2突变；（c）10例因无存档材料而被排除在分析之外。最终队列分别包括4名和14名携带BRCA1和BRCA2突变的男性。我们使用来自显微切割肿瘤的DNA的多重连接依赖探针扩增来检测BRCA1和BRCA2基因的LOH。
在14名BRCA2突变携带者的肿瘤中有10例观察到BRCA2的LOH（71%），而在4名BRCA1突变携带者的肿瘤中未观察到BRCA1的LOH（P = 0.02）。假设LOH仅因为癌症是由种系突变引起的，那么携带BRCA2突变的人患前列腺癌的风险增加3.5倍（95%置信区间，1.8 - 12）。高Gleason评分是唯一明显的临床特征。
这些观察结果与BRCA2而非BRCA1是前列腺癌肿瘤抑制基因的观点一致。
