Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings
Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings
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DOI：
10.1158/1078-0432.ccr-16-0015
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发表时间：
2016-08-15
影响因子：
11.5
通讯作者：
Berg, Jonathan S.
中科院分区：
文献类型：
--
作者：
Seifert, Bryce A.;O'Daniel, Julianne M.;Berg, Jonathan S.
目的：评价接受肿瘤-种系测序的非选择性癌症患者中遗传癌症易感基因的种系变异。实验设计：通过LCCC1108/UNCseq (TM) （NCT01457196）研究对439例个体进行肿瘤-种系二联体测序，分析36个遗传性癌症易感基因的遗传变异。这些变异作为一项探索性研究进行分析，以确定在接受肿瘤-种系测序的患者的种系中是否存在致病变异。患者在遗传癌症易感性指标方面未被选择。结果：在19例（4.3%）患者中发现了指示遗传性癌症易感性的变异。对于大约一半（10/19），这些发现代表了新的诊断信息，对患者及其家属具有潜在的重要意义。其他的是先前通过继发于怀疑遗传癌症易感性的临床遗传评估确定的。致病变异的基因包括ATM、BRCA1、BRCA2、CDKN2A和CHEK2。相比之下，相当大比例的患者（178,40.5%）具有不确定意义变异（VUS），其中24例在与呈现癌相关的基因中具有VUS。另外143人在其他遗传性癌症基因中有VUS， 11人在相关和非相关基因中都有VUS。结论：肿瘤-生殖系测序双体的生殖系分析偶尔会揭示临床隐匿的重要生殖系发现，这可能对患者及其家属有益。然而，考虑到意外生殖系变异的低产出率和VUS结果患者的很大比例，生殖系结果的分析和返回应遵循继发性发现的指南，而不是诊断性遗传性癌症检测。(c) 2016年aacr。
Purpose: To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing.Experimental Design: Germline sequence data from 439 individuals undergoing tumor-germline dyad sequencing through the LCCC1108/UNCseq (TM) (NCT01457196) study were analyzed for genetic variants in 36 hereditary cancer susceptibility genes. These variants were analyzed as an exploratory research study to determine whether pathogenic variants exist within the germline of patients undergoing tumor-germline sequencing. Patients were unselected with respect to indicators of hereditary cancer predisposition.Results: Variants indicative of hereditary cancer predisposition were identified in 19 (4.3%) patients. For about half (10/19), these findings represent new diagnostic information with potentially important implications for the patient and their family. The others were previously identified through clinical genetic evaluation secondary to suspicion of a hereditary cancer predisposition. Genes with pathogenic variants included ATM, BRCA1, BRCA2, CDKN2A, and CHEK2. In contrast, a substantial proportion of patients (178, 40.5%) had Variants of Uncertain Significance (VUS), 24 of which had VUS in genes pertinent to the presenting cancer. Another 143 had VUS in other hereditary cancer genes, and 11 had VUS in both pertinent and nonpertinent genes.Conclusions: Germline analysis in tumor-germline sequencing dyads will occasionally reveal significant germline findings that were clinically occult, which could be beneficial for patients and their families. However, given the low yield for unexpected germline variation and the large proportion of patients with VUS results, analysis and return of germline results should adhere to guidelines for secondary findings rather than diagnostic hereditary cancer testing. (C) 2016 AACR.