Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.
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DOI：
10.1001/jamaoncol.2015.5208
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发表时间：
2016-01
期刊：
影响因子：
28.4
通讯作者：
Robson M
中科院分区：
文献类型：
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作者：
Schrader KA;Cheng DT;Joseph V;Prasad M;Walsh M;Zehir A;Ni A;Thomas T;Benayed R;Ashraf A;Lincoln A;Arcila M;Stadler Z;Solit D;Hyman DM;Zhang L;Klimstra D;Ladanyi M;Offit K;Berger M;Robson M
肿瘤基因测序鉴定具有治疗意义的潜在靶向遗传改变。分析集中在检测肿瘤特异性变体上，但种系变体的识别也可能被证明是有价值的。估计通过常规临床肿瘤测序鉴定的生殖系变异的负荷。符合Memorial Sloan Kettering癌症中心靶向药物研究条件的晚期癌症诊断患者可使用341个基因组MSK-IMPACT进行肿瘤正常测序。我们调查了在2014年3月至10月期间接受肿瘤分析的1566名患者中187个与孟德尔疾病相关的重叠基因中观察到的种系变异。在与单基因疾病相关的187个基因中，每个人的假定致病性生殖系变异（PPGV）和不确定意义的变异的数量，以及在临床相关基因亚群中，在与已知肿瘤表型一致的基因中，以及在肿瘤中有第二次体细胞命中证据的基因中，PPGV个体的比例。1566例患者的平均年龄为58岁，54%为女性。在1566例患者中，有246例（15.7%; 95%CI，14.0%-17.6%）确定了已知孟德尔疾病相关基因中的假定致病性种系变异，其中包括198例与癌症易感性相关基因突变的个体。在198例病例中，只有81例（40.9%; 95%CI，34.3%-47.9%）的癌症易感基因的生殖系发现与个体的癌症类型一致。在肿瘤中保留PPGV的个体中，在182例病例中的39例中观察到另一等位基因的体细胞改变（21.4%; 95%CI，16.1%-28.0%），其中13例未显示生殖系突变与已知综合征的已知相关性。在1566例病例中，55例（3.5%; 95%CI，27.1%-45.4%）观察到非癌症相关孟德尔疾病基因突变。几乎每个个体都有1个以上不确定意义的变异（1566例患者中的1565例; 99.9%; 95% CI，99.6%-99.9%）。生殖系变异在接受肿瘤正常测序的个体中很常见，并且可能揭示其他未被怀疑的综合征关联。
Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. To estimate the burden of germline variants identified through routine clinical tumor sequencing. Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%–17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual’s cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%–47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%–28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non–cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%–45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99.9%; 95% CI, 99.6%–99.9%). Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.