Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing.
Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing.
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DOI：
10.1186/s12920-017-0271-4
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发表时间：
2017-05-19
影响因子：
2.7
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Cheng DT;Prasad M;Chekaluk Y;Benayed R;Sadowska J;Zehir A;Syed A;Wang YE;Somar J;Li Y;Yelskaya Z;Wong D;Robson ME;Offit K;Berger MF;Nafa K;Ladanyi M;Zhang L
越来越多的下一代测序（NGS）测试正在改变遗传性癌症的常规临床诊断。确定癌症是否是癌症易感基因中潜在致病突变的结果，不仅可以诊断癌症易感综合征，而且对患者及其家属的临床管理具有重要的临床意义。在这里，我们评估了MSK-IMPACT（纪念斯隆-凯特琳-可操作癌症靶点的综合突变分析）在检测与癌症易感综合征有关的76个基因的遗传改变方面的性能。在Illumina HiSeq 2500上对来自基于杂交的捕获的输出进行测序。使用定制分析管道来检测单核苷酸变体（SNV）、小插入/缺失（indel）和拷贝数变体（CNV）。MSK-IMPACT在一组233个独特的患者DNA样本中检测到了所有种系变异，这些样本先前已通过先前的单基因检测得到证实。使用运行间和运行内重复证明了变异调用的重现性。此外，在16个样本中，我们确定了除先前通过传统的逐基因方法确定的致病性突变之外的其他致病性突变，包括BRCA 1、BRCA 2、CHEK 2和APC中的创始者突变，以及TP 53、TSC 2、ATM和VHL中的截短突变。这项研究强调了基于NGS的基因组检测方法在全面鉴定导致癌症易感性的种系变异和同时检测体细胞和种系改变方面的重要性。本文的在线版本（doi：10.1186/s12920-017-0271-4）包含补充材料，可供授权用户使用。
The growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families. Here, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes. Output from hybridization-based capture was sequenced on an Illumina HiSeq 2500. A custom analysis pipeline was used to detect single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants (CNVs). MSK-IMPACT detected all germline variants in a set of 233 unique patient DNA samples, previously confirmed by previous single gene testing. Reproducibility of variant calls was demonstrated using inter- and intra- run replicates. Moreover, in 16 samples, we identified additional pathogenic mutations other than those previously identified through a traditional gene-by-gene approach, including founder mutations in BRCA1, BRCA2, CHEK2 and APC, and truncating mutations in TP53, TSC2, ATM and VHL. This study highlights the importance of the NGS-based gene panel testing approach in comprehensively identifying germline variants contributing to cancer predisposition and simultaneous detection of somatic and germline alterations. The online version of this article (doi:10.1186/s12920-017-0271-4) contains supplementary material, which is available to authorized users.