Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families
Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families
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DOI：
10.1086/301749
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发表时间：
1998-03-01
影响因子：
9.8
通讯作者：
Vasen, H
中科院分区：
文献类型：
--
作者：
Ford, D;Easton, DF;Vasen, H
BRCA1和BRCA2对遗传性乳腺癌的贡献通过连锁和突变分析评估了237个家庭，每个家庭至少有4例乳腺癌，由乳腺癌连锁联盟收集。总体而言，估计52%的家族与BRCA1有关，32%的家族与BRCA2有关，16%的家族与任何基因都无关（95%置信区间[CI] 6%-28%），这表明其他易感基因。大多数（81%）的乳腺癌家族是由BRCA1引起的，其他大多数（14%）是由BRCA2引起的。相反，大多数患有男性和女性乳腺癌的家庭都是由于BRCA2（76%）。由于其他基因导致的最大比例（67%）的家庭仅在有4或5例女性乳腺癌的家庭中发现，这些估计不会因改变BRCA1的假设外显率模型或包括或排除BRCA1突变数据而受到实质性影响。在通过一种标准筛选方法检测BRCA1所致疾病的家庭中，估计有63%的人在编码序列或剪接位点检测到突变（95% CI 51%-77%）。估计灵敏度与直接测序和其他技术相同。在所有可能的外显率函数中，BRCA2的外显率通过最大化BRCA2突变家族的LOD评分来估计，到50岁时乳腺癌的估计累积风险达到28% (95% CI为9%-44%)，到70岁时达到84% （95% CI为43%-95%）。相应的50岁时卵巢癌风险为0.4% (95% CI 0%-1%)， 70岁时为27% （95% CI 0%-47%）。乳腺癌的终生风险与BRCA1携带者相似，但有迹象表明BRCA2携带者的风险较低
The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers, Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes, The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due To BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes tvas found in families with four or five cases of female breast cancer only, These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated bg maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions, The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 pears. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years, The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers