通过检验发现癌症的BRCA2基因突变
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By LabMedica International staff writers Posted on 19 Mar 2018 |
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图片：子宫内膜样卵巢癌显示BRCA2的核染色（右半部）；子宫内膜样卵巢癌BRCA2阴性染色（左半部）（图片蒙德克萨斯大学MD安德森癌症中心惠赐）。
临床基因检验发现了乳腺癌易感基因2 (BRCA2)的许多意义不明变异(VUS)。VUS形成一项严重的临床挑战，因为这些变体对癌症风险的促进作用尚不明确。
刚开发成功的一款检验产品能显示BRCA2基因里的哪些突变使妇女易生乳腺癌或卵巢癌。这款基于实验室的检验产品能确定BRCA2基因里的哪些遗传性VUS突变与癌症形成有关。
美国明尼苏达州罗彻斯特市梅奥诊所的科学家及其同事使用经过确证的BRCA2同源重组(HR) DNA修复活性的功能性测定全面评估了BRCA2 C末端DNA结合域(DBD)里的VUS，并定义了变异致病性的分类器。
在评估的139种变异中，54种的致病概率大于等于99%，73种的中性概率大于等于95%。比较功能性测定的结果与Align-GVGD蛋白序列预测算法预测变异致病性的结果，该算法以前一直用于变异的分类。相较HR测定，Align-GVGD预测的致病变异严重过头。
科研小组随后在一个贝叶斯分级模型(VarCall)中结合功能性测定与Align-GVGD的预测结果，估计每种VUS的总体致病概率。此外，为了预测所有其它BRCA2 DBD变异的作用，并优选供功能性研究的变异，他们用内表现型优化的序列集合(endoPhenotype-Optimized Sequence Ensemble, ePOSE)算法和HR功能性测定的数据训练BRCA2变异的分类器。
这项研究的高级研究员Fergus J. Couch博士说：“迄今为止，我们只能确定BRCA2基因中的13个遗传性突变致癌。本次研究发现了54种突变会增加癌症风险。已知不会增加癌症风险的21个中性突变现在增加到73个。这些发现也许能帮助患者和医院更好地决定如何处理基因检验获得的信息。”该研究的论文发表于2018年1月25日的《美国人类遗传学杂志》(American Journal of Human Genetics)。
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梅奥诊所
刚开发成功的一款检验产品能显示BRCA2基因里的哪些突变使妇女易生乳腺癌或卵巢癌。这款基于实验室的检验产品能确定BRCA2基因里的哪些遗传性VUS突变与癌症形成有关。
美国明尼苏达州罗彻斯特市梅奥诊所的科学家及其同事使用经过确证的BRCA2同源重组(HR) DNA修复活性的功能性测定全面评估了BRCA2 C末端DNA结合域(DBD)里的VUS，并定义了变异致病性的分类器。
在评估的139种变异中，54种的致病概率大于等于99%，73种的中性概率大于等于95%。比较功能性测定的结果与Align-GVGD蛋白序列预测算法预测变异致病性的结果，该算法以前一直用于变异的分类。相较HR测定，Align-GVGD预测的致病变异严重过头。
科研小组随后在一个贝叶斯分级模型(VarCall)中结合功能性测定与Align-GVGD的预测结果，估计每种VUS的总体致病概率。此外，为了预测所有其它BRCA2 DBD变异的作用，并优选供功能性研究的变异，他们用内表现型优化的序列集合(endoPhenotype-Optimized Sequence Ensemble, ePOSE)算法和HR功能性测定的数据训练BRCA2变异的分类器。
这项研究的高级研究员Fergus J. Couch博士说：“迄今为止，我们只能确定BRCA2基因中的13个遗传性突变致癌。本次研究发现了54种突变会增加癌症风险。已知不会增加癌症风险的21个中性突变现在增加到73个。这些发现也许能帮助患者和医院更好地决定如何处理基因检验获得的信息。”该研究的论文发表于2018年1月25日的《美国人类遗传学杂志》(American Journal of Human Genetics)。
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