Bhai Pratibha, Levy Michael A, Rooney Kathleen, Carere Deanna Alexis, Reilly Jack, Kerkhof Jennifer, Volodarsky Michael, Stuart Alan, Kadour Mike, Panabaker Karen, Schenkel Laila C, Lin Hanxin, Ainsworth Peter, Sadikovic Bekim
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Front Genet. 2021 Jul 13;12:698595. doi: 10.3389/fgene.2021.698595. eCollection 2021.
Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient's personal and/or family history of cancer.
A 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).
A 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.
This study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.
遗传性癌症易感性综合征约占癌症病例的10%。基于新一代测序（NGS）的多基因靶向检测板现在是识别高危家族中癌症易感基因致病突变的一线方法。NGS技术的最新发展使得能够在单个平台上同时检测序列和拷贝数变异（CNV）。在本研究中，我们分析了加拿大一组疑似遗传性癌症综合征患者的序列变异和CNV的频率及性质，这些患者根据患者个人和/或家族癌症病史，按照特定的基因检测指南转诊进行基因检测。
2870名患者在安大略西南部的我们的参考实验室接受了基于单一NGS的多基因靶向遗传性癌症检测板检测算法，以识别癌症易感基因中的序列变异和CNV。通过NGS鉴定的CNV通过多重连接依赖探针扩增（MLPA）等替代技术进行确认。
15%（431/2870）的患者在癌症易感基因中有致病变异，36%（1032/2870）有意义未明的变异（VUS）。总共鉴定出287个独特的致病变异，其中23个（8%）是新的。基于NGS方法鉴定的CNV占致病变异的9.5%（27/287），经替代技术高度准确地确认。
本研究强调了基于NGS的靶向检测方法在临床环境中识别疑似遗传性癌症综合征患者的序列变异和CNV的实用性，并扩展了高和中度外显率癌症易感基因的突变谱。
