Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland.
Cancer Genetics Unit, The Royal Marsden NHS Foundation Trust, London, UK.
Ir J Med Sci. 2020 Aug;189(3):849-864. doi: 10.1007/s11845-020-02174-x. Epub 2020 Feb 1.
Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer.
A custom panel comprising 83 genes offered by 19 clinical "breast cancer predisposition" MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline.
Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls. Most variants identified were in genes associated with predisposition to cancers other than breast cancer (BRIP1, RAD50, MUTYH, and mismatch repair genes), or in genes with unknown or unproven association with cancer.
Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.
乳腺癌在遗传上具有异质性，并行多基因测序是研究乳腺癌易感性最具成本效益和时间效益的方法。许多多基因检测面板（MGPs）可在商业上获得，但其中许多包括与乳腺癌关联较弱/未经证实的基因，或与其他类型癌症易感性相关的基因。本研究调查了在爱尔兰乳腺癌患者队列中使用定制多基因面板的效用。
设计了一个由 19 种临床“乳腺癌易感性”MGPs 提供的 83 个基因组成的定制面板，并将其应用于 91 例乳腺癌患者和 77 例无血缘关系的种族匹配对照者的种系 DNA。使用定制管道识别和分类变体。
鉴定出 19 种功能丧失（LOF）和 334 种错义变体。去除常见和/或良性变体后，分析了 15 种 LOF 和 30 种错义变体。在病例中鉴定出已知乳腺癌易感性基因中的变体，包括 BRCA1 和 ATM，在对照中鉴定出 NF1 和 CHEK2。大多数鉴定出的变体位于与乳腺癌以外癌症易感性相关的基因中（BRIP1、RAD50、MUTYH 和错配修复基因），或位于与癌症关联未知或未经证实的基因中。
使用多基因面板可以快速、经济有效地鉴定出具有高风险癌症易感性综合征的个体。然而，这种方法也会导致不确定结果的增加。在没有匹配表型/家族史的情况下，对具有特定遗传变异的个体进行临床管理具有挑战性。需要进一步的人群和功能证据来充分阐明不确定意义基因变异的临床相关性。
