文章：

遗传性乳腺癌和卵巢癌：局限通路中的新基因

Hereditary breast and ovarian cancer: new genes in confined pathways

原文发布日期：2016-08-12

DOI: 10.1038/nrc.2016.72

类型: Review Article

开放获取: 否

要点：

1. Genetic abnormalities in BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of HBOC cases can be ascribed to BRCA1 and BRCA2 mutations.
2. Next-generation sequencing approaches are uncovering novel HBOC factors among affected families without BRCA1 or BRCA2 mutations; at present more than 25 have emerged. New factors generally function in the same genome maintenance pathways as established HBOC factors, indicating substantial locus heterogeneity.
3. Disabled pathways in HBOC are homologous recombination repair (HRR), protection of stalling DNA replication forks, mismatch repair, and cell cycle checkpoint and DNA damage checkpoint control pathways.
4. The new pathogenic variants are rare, which poses challenges to the estimation of risk attribution through patient cohorts. There is a risk that patients or healthy carriers exhibiting pathogenic variants in rare HBOC genes may be excluded from the best possible treatment or presymptomatic screening programmes.
5. Structural and functional analysis can support variant classification in the context of international collaboration and standardized guidelines. Functional approaches are aided by extensive locus heterogeneity, which converges on a relatively small number of genome maintenance pathways that may be reconciled in vitro.

要点翻译：

1. BRCA1和BRCA2基因的异常易导致遗传性乳腺癌和卵巢癌（HBOC）。然而，仅有约25%的HBOC病例可归因于BRCA1和BRCA2突变。
2. 新一代测序技术正在未携带BRCA1或BRCA2突变的患病家族中发现新的HBOC致病因子；目前已有超过25个新因子被确认。这些新因子通常与已知HBOC因子作用于相同的基因组维护通路，表明该疾病存在显著的基因座异质性。
3. HBOC中失活的通路包括同源重组修复（HRR）、停滞DNA复制叉的保护、错配修复、细胞周期检查点及DNA损伤检查点控制通路。
4. 新的致病性变异较为罕见，这为通过患者队列进行风险归因评估带来了挑战。携带罕见HBOC基因致病性变异的患者或健康携带者，可能无法获得最佳治疗方案或症状前筛查计划。
5. 在国际合作和标准化指南框架下，结构和功能分析可为变异分类提供支持。广泛存在的基因座异质性有助于功能学研究方法的开展——这些异质性最终汇聚于数量相对较少的基因组维护通路，并可在体外实验中得以验证。

英文摘要：

Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making.

摘要翻译： 

DNA修复基因BRCA1和BRCA2的遗传异常易导致遗传性乳腺癌和卵巢癌（HBOC）。然而，仅有约25%的HBOC病例可归因于BRCA1和BRCA2突变。近年来，外显子组测序在无BRCA1或BRCA2突变的受累家族中发现了显著的基因座异质性。新的致病变异较为罕见，通过患者队列估计风险归因面临挑战。本文综述了HBOC基因，重点关注其在基因组维持中的作用、对推定因果变异进行功能检测的可能性，以及新的HBOC基因在癌症风险管理和治疗决策中的临床应用。

原文链接：

Hereditary breast and ovarian cancer: new genes in confined pathways