利用配对正常 DNA 进行靶向肿瘤测序中的种系变异。
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.
机构信息
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada3Department of Medical Genetics, University of British Columbia, Vancouver, British C.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
出版信息
JAMA Oncol. 2016 Jan;2(1):104-11. doi: 10.1001/jamaoncol.2015.5208.
IMPORTANCE
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.
OBJECTIVE
To estimate the burden of germline variants identified through routine clinical tumor sequencing.
DESIGN, SETTING, AND PARTICIPANTS: 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.
MAIN OUTCOMES AND MEASURES
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.
RESULTS
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%).
CONCLUSIONS AND RELEVANCE
Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.
重要性
肿瘤基因测序可识别具有治疗意义的潜在靶向遗传改变。分析主要集中在检测肿瘤特异性变异，但识别种系变异也可能具有重要价值。
目的
评估通过常规临床肿瘤测序确定的种系变异的负担。
设计、地点和参与者：在纪念斯隆凯特琳癌症中心接受靶向药物研究的晚期癌症患者可选择进行肿瘤-正常测序，采用 MSK-IMPACT 341 基因检测面板。我们对 2014 年 3 月至 10 月期间进行肿瘤分析的 1566 名患者的 187 个与孟德尔疾病相关且具有明确疾病关联的重叠基因中的种系变异进行了调查。
主要结果和措施
187 个与单基因疾病相关的基因中每个人的假定致病性种系变异（PPGVs）和意义不明的变异数量，以及在临床上相关的基因亚组、与已知肿瘤表型一致的基因和在肿瘤中具有第二个体细胞突变证据的基因中具有 PPGVs 的个体比例。
结果
1566 名患者的平均年龄为 58 岁，54%为女性。在 1566 名患者中的 246 名（15.7%；95%置信区间，14.0%-17.6%）中发现了已知孟德尔疾病相关基因中的假定致病性种系变异，包括 198 名个体存在癌症易感性相关基因的突变。在 198 例中，种系发现与癌症易感性基因仅在 81 例（40.9%；95%置信区间，34.3%-47.9%）中与个体的癌症类型一致。在保留在肿瘤中的 PPGVs 个体中，另一个等位基因的体细胞改变见于 182 例中的 39 例（21.4%；95%置信区间，16.1%-28.0%），其中 13 例没有已知的种系突变与已知综合征的相关性。在 1566 例中，55 例（3.5%；95%置信区间，27.1%-45.4%）中存在非癌症相关孟德尔疾病基因的突变。几乎每个个体都有不止一个意义不明的变异（1565 例中的 1566 例；99.9%；95%置信区间，99.6%-99.9%）。
结论和相关性
种系变异在进行肿瘤-正常测序的个体中很常见，可能揭示出其他未被怀疑的综合征关联。
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