Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management.
Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management.
复制标题
多基因面板的临床应用：下一代咨询和癌症风险管理的挑战。
DOI：
10.3389/fonc.2015.00208
复制
发表时间：
2015
影响因子：
4.7
通讯作者：
Weitzel JN
中科院分区：
文献类型：
--
作者：
Slavin TP;Niell-Swiller M;Solomon I;Nehoray B;Rybak C;Blazer KR;Weitzel JN
多基因面板可以是一个成本和时间有效的替代顺序测试多个基因，特别是与混合家族癌症表型。然而，超越单基因测试范式给临床医生带来了许多新的挑战。这篇文章的目的是让读者熟悉一些挑战，以及潜在的机会，扩大遗传性癌症小组测试。我们纳入了2014年1月1日至2014年10月1日期间由City of Hope的临床癌症遗传学实践社区相关的临床医生订购的348个商业多基因面板测试的结果。我们还讨论了在此期间出现的涉及基因异常的特定挑战性病例：CDH1， TP53, PMS2, PALB2, CHEK2， NBN和RAD51C。如果仅将历史上的高风险基因（BRCA1, BRCA2, MSH6, PMS2, TP53， APC, CDH1）包括在面板中，那么结果只有6.2%的时间是阳性的，而不是17%。42%的时间返回的结果具有不确定意义的变异（VUS）。这些数字和案例强调了充分的检测前咨询的重要性，因为预计阳性、VUS、意外和模糊的检测结果的百分比会更高。使用表型特异性面板可以限制测试结果的模糊性；如果发现，可以使用多种资源（文献、参考实验室、同事、国家专家和研究成果）来更好地为患者和家属澄清咨询和管理。对于低风险和中等风险基因的致病变异，基于患者个人和家族癌症史的经验风险模型可能取代基因特异性风险。商业实验室和患者对公共数据库和研究工作的贡献将需要更好地分类变异和减少多基因面板的临床模糊性。
Multigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing. We include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope’s Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C. If historically high risk genes only were included in the panels (BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time. These figures and cases stress the importance of adequate pre-test counseling in anticipation of higher percentages of positive, VUS, unexpected, and ambiguous test results. Test result ambiguity can be limited by the use of phenotype-specific panels; if found, multiple resources (the literature, reference laboratory, colleagues, national experts, and research efforts) can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient’s personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels.