Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation
Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation
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DOI：
10.1158/1078-0432.ccr-07-5237
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Thorne, Heather J.
中科院分区：
文献类型：
--
作者：
Willems, Amber J.;Dawson, Sarah-Jane;Thorne, Heather J.
目的：携带BRCA2和BRCA1致病种系突变的男性患前列腺癌的风险增加。我们的主要目的是检测携带BRCA1或BRCA2致病性种系突变的男性前列腺癌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。实验设计：从1243个kCon Fab家族中：(a) 215个家族携带致病性BRCA1突变，而188个家族携带致病性BRCA2突变；(b)在被诊断患有前列腺癌的158名男性（来自137个家族）中，8人被证实携带家族特异性BRCA1突变，而20人被证实携带家族特异性BRCA2突变；(c)由于没有档案材料，10个病例被排除在分析之外。最后一组分别由4名和14名携带BRCA1和BRCA2突变的男性组成。我们使用多重连接依赖探针扩增来自微解剖肿瘤的DNA来检测BRCA1和BRCA2基因的LOH。结果：来自BRCA2突变携带者的14个肿瘤中有10个（71%）观察到BRCA2位点的LOH，而来自BRCA1突变携带者的4个肿瘤中未观察到BRCA1位点的LOH （P = 0.02）。假设LOH的发生仅仅是因为癌症是由种系突变引起的，BRCA2突变携带者患前列腺癌的风险增加了3.5倍（95%置信区间，1.8-12）。唯一明显的临床特征是高格里森指数。结论：这些观察结果与BRCA2而非BRCA1是前列腺癌肿瘤抑制因子的观点一致。
Purpose: 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.Experimental Design: From 1,243 kCon Fab 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.Results: 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.Conclusions: These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.