The contribution of germline rearrangements to the spectrum of BRCA2 mutations
The contribution of germline rearrangements to the spectrum of BRCA2 mutations
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DOI：
10.1136/jmg.2005.040212
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Tosi, M.
中科院分区：
文献类型：
--
作者：
Casilli, F.;Tournier, I.;Tosi, M.
背景：与 BRCA1 基因中报道的大量种系重排相比，很少有种系 BRCA2 重排被描述。然而，在至少包括一例男性乳腺癌的家族中已报道了一些 BRCA2 重排。 目的：估计大基因组重排对 BRCA2 缺陷谱的贡献。方法：使用短荧光片段定量多重 PCR (QMPSF) 在精心选择的家庭中筛选 BRCA2 基因的种系重排。 QMPSF 之前被用于检测包括 BRCA1 和 BRCA2 在内的许多基因的杂合性缺失/重复。 结果：我们选择了 194 个患有 4 种或以上乳腺癌的高危家庭，平均诊断年龄为 50 岁，通过法国 14 个遗传咨询中心和瑞士 1 个中心招募。18.6% 检测到 BRCA2 突变（36 个指标病例），12.4% 检测到 BRCA1 突变。在该亚组的 134 个 BRCA1/2 阴性指示病例中，使用 QMPSF 对 120 个进行了 BRCA2 大型重排筛查，在三个家庭中检测到了新的、独特的 BRCA2 缺失，并确定了其边界。结论：乳腺癌易感性的分子诊断。应包括筛查 BRCA2 重排，至少在 BRCA2 缺陷可能性较高的家庭中如此。
Background: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer.Objective: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects.Methods: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2.Results: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of (50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum.Conclusion: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.