Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines
Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines
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DOI：
10.1016/j.jmoldx.2019.03.001
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发表时间：
2019-07-01
影响因子：
4.1
通讯作者：
Zhou, Alicia Y.
中科院分区：
文献类型：
--
作者：
Neben, Cynthia L.;Zimmer, Anjali D.;Zhou, Alicia Y.
下一代测序的最新进展极大地扩展了多基因面板测试对遗传性癌症风险的使用。虽然基因检测有助于指导临床诊断和管理，但检测建议是基于个人和家族癌症史和种族，许多携带者被遗漏。在本文中，我们报告了23，179名个体的结果，这些个体被转介进行30个基因的下一代测序面板检测遗传性癌症风险，独立于当前的检测指南-38.7%的个体不符合国家综合癌症网络基因检测标准。我们在2698名个体中共鉴定出2811种致病性变异，总体致病性频率为11.6/0（9.1%，不包括常见的低等位基因）。在德系犹太人后裔中，四分之三的致病性变异在三个常见的BRCA 1和BRCA 2创始等位基因之外。在所有种族群体中，BRCA 1和BRCA 2的致病性变异发生频率最高，但其他基因中致病性变异的贡献各不相同。最后，我们发现，21.7%的基因中有致病性变异的个体，其基因检测建议已得到确认，但不符合相应的国家综合癌症网络标准。总的来说，结果表明，更多的人有遗传性癌症的遗传风险，而不是通过目前的检测指南和/或使用单基因或单位点检测确定的。
Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene panel testing for hereditary cancer risk. Although genetic testing helps guide clinical diagnosis and management, testing recommendations are based on personal and family history of cancer and ethnicity, and many carriers are being missed. Herein, we report the results from 23,179 individuals who were referred for 30-gene next-generation sequencing panel testing for hereditary cancer risk, independent of current testing guidelines-38.7% of individuals would not have met National Comprehensive Cancer Network criteria for genetic testing. We identified a total of 2811 pathogenic variants in 2698 individuals for an overall pathogenic frequency of 11.6/0 (9.1%, excluding common low-penetrance alleles). Among individuals of Ashkenazi Jewish descent, three-quarters of pathogenic variants were outside of the three common BRCA1 and BRCA2 founder alleles. Across all ethnic groups, pathogenic variants in BRCA1 and BRCA2 occurred most frequently, but the contribution of pathogenic variants in other genes on the panel varied. Finally, we found that 21.7% of individuals with pathogenic variants in genes with well-established genetic testing recommendations did not meet corresponding National Comprehensive Cancer Network criteria. Taken together, the results indicate that more individuals are at genetic risk for hereditary cancer than are identified by current testing guidelines and/or use of single-gene or single-site testing.