Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
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DOI：
10.1053/j.gastro.2015.05.006
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发表时间：
2015-09
期刊：
影响因子：
29.4
通讯作者：
Syngal S
中科院分区：
文献类型：
--
作者：
Yurgelun MB;Allen B;Kaldate RR;Bowles KR;Judkins T;Kaushik P;Roa BB;Wenstrup RJ;Hartman AR;Syngal S
多基因板是用于遗传性癌症风险评估的商业化工具，其允许并行地对许多基因进行下一代测序。然而，目前尚不清楚这些小组是否比传统的基因检测具有优势。我们调查了在疑似Lynch综合征患者中通过平行测序鉴定的癌症易感基因突变的数量。我们使用25个基因的下一代测序面板进行了种系分析，使用了2012年至2013年接受林奇综合征临床基因检测的1260名个体的DNA。所有受试者均有Lynch综合征相关癌症和/或息肉病史。我们对所有确定的生殖系致病性改变进行了分类，并计算了致病性突变和不确定意义变异（VUS）的频率。我们还分析了患者个人和家族癌症史的数据，包括基因检测临床指南的履行情况。在1260例受试者中，1112例符合国家综合癌症网络（NCCN）Lynch综合征测试标准（88%; 95%置信区间[CI]，86%-90%）。多基因面板测试确定了114名Lynch综合征突变的先证者（9.0%; 95% CI，7.6%-10.8%）和71名其他癌症易感基因突变的先证者（5.6%; 95% CI，4.4%-7.1%）。15个个体有BRCA 1或BRCA 2突变;其中93%符合林奇综合征检测的NCCN标准，33%符合BRCA 1和BRCA 2分析的NCCN标准（P= 0.0017）。另外9名患者携带与癌症高终身风险相关的其他基因突变（5名APC突变，3名MUTYH双等位基因突变，1名STK 11突变）;所有这些患者均符合林奇综合征测试的NCCN标准。479例患者有≥1个VUS（38%; 95% CI，35%-41%）。在疑似Lynch综合征的个体中，多基因面板测试确定了癌症易感基因中的高突变率突变，其中许多是基于患者的病史而意外的。平行测序还检测到大量潜在的无信息生殖系发现，包括VUS。
Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All subjects had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain significance (VUS). We also analyzed data on patients’ personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 subjects, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%–90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%−10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%−7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P=.0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. Four hundred seventy-nine individuals had ≥1 VUS (38%; 95% CI, 35%–41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients’ histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.