Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol
Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol
复制标题
DOI：
10.1093/annonc/mdw018
复制
发表时间：
2016-05-01
影响因子：
50.5
通讯作者：
Chen, K.
中科院分区：
文献类型：
--
作者：
Meric-Bernstam, F.;Brusco, L.;Chen, K.
我们在研究实验室利用肿瘤和正常DNA对1000例晚期癌症患者的202个基因进行了靶向外显子组测序。患者被问及是否对致病种系变异的回报感兴趣。评估了19个被认为可采取行动的基因的致病变异频率。在一个正交CLIA平台上证实了先前未知的变异。通过正式的遗传咨询返回结果。癌症研究中的下一代测序可能揭示临床意义的种系变异。我们报告了患者对结果返回的偏好和附带致病性种系变异（PGVs）的患病率。在一个研究实验室中，利用肿瘤和正常DNA对1000例晚期癌症患者的202个基因进行了靶向外显子组测序。美国医学遗传学和基因组学学院以及PALB2推荐的18个基因的致病变异被认为是可采取行动的。收集患者对附带生殖系结果的偏好。通过遗传咨询和重复CLIA检测开始返回结果。在接受测序的1000名患者中，43名可能患有pgv: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2(1)和RB1(1)。43个变异中有20个（47%）以前是基于临床基因检测而已知的。在1167名同意生殖系检测方案的患者中，1157名（99%）希望被告知附带结果。在研究环境中发现的23个先前未被识别的突变通过正交CLIA平台得到证实。所有接触的患者都决定进行正式的遗传咨询；在所有进行了正式基因检测的病例中，临床基因检测证实了所关注的种系变异。在这一系列研究中，2.3%的患者在19种癌症相关基因中存在先前未被识别的致病性种系突变。因此，基因组测序必须伴随着生殖细胞结果的返回计划，并与遗传咨询合作。
We carried out targeted exome sequencing of 202 genes in 1000 advanced cancer patients using tumor and normal DNA in a research laboratory. Patients were asked about their interest in return of pathogenic germline variants. The frequency of pathogenic variants in 19 genes that were considered actionable was assessed. Previously unknown variants were confirmed on an orthogonal CLIA platform. Return of results with formal genetic counseling was initiated.Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs).Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing.In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.