Department of Cancer Biology & Genetics and Division of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA.
J Med Genet. 2017 Nov;54(11):721-731. doi: 10.1136/jmedgenet-2017-104707. Epub 2017 Sep 2.
Mutation of and is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As reviewed here, both of these tumour suppressors promote the maintenance of genome stability via homologous recombination. Thus, related assays may be particularly relevant to cancer risk. Progress in implementing functional assays to assess missense variants of BRCA1 and BRCA2 is considered here, along with current limitations and the path to more impactful assay systems. While functional assays have been developed to independently evaluate BRCA1 and BRCA2 VUS, high-throughput assays with sufficient sensitivity to characterise the large number of identified variants are lacking. Additionally, because of relatively low conservation of certain domains of BRCA1, and of BRCA2, between humans and rodents, heterologous expression in rodent cells may have limited reliability or capacity to assess variants present throughout either protein. Moving forward, it will be important to perform assays in human cell lines with relevance to particular tumour types, and to strengthen risk predictions based on multifactorial statistical analyses that also include available data on cosegregation and tumour pathology.
和 的突变是遗传性乳腺癌和卵巢癌最常见的原因。检测变异携带者的遗传筛查可以通过识别癌症风险较高的个体来帮助预防癌症，并有可能用于预测肿瘤对治疗的反应性。通常，无法基于传统方法（如分离分析）进行分类，包括许多错义变异，因此这些变异被称为意义不明的变异（VUS）。功能测定为 BRCA1 和 BRCA2 VUS 的分类提供了重要的替代方法。如本文所述，这两种肿瘤抑制因子都通过同源重组促进基因组稳定性的维持。因此，相关的测定方法可能与癌症风险特别相关。本文考虑了实施功能测定来评估 BRCA1 和 BRCA2 错义变异的进展，以及当前的局限性和更具影响力的测定系统的途径。虽然已经开发了功能测定来独立评估 BRCA1 和 BRCA2 的 VUS，但缺乏具有足够灵敏度来描述大量已识别变异的高通量测定。此外，由于 BRCA1 和 BRCA2 的某些结构域在人类和啮齿动物之间相对保守性较低，因此在啮齿动物细胞中异源表达可能具有有限的可靠性或评估整个蛋白质中存在的变异的能力。向前推进，在与特定肿瘤类型相关的人细胞系中进行测定并基于包括共分离和肿瘤病理学的可用数据的多因素统计分析来加强风险预测将非常重要。
