Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing

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 s...

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Published in:	BMC medical genomics Vol. 10; no. 1; p. 33
Main Authors:	Cheng, Donavan T, Prasad, Meera, Chekaluk, Yvonne, Benayed, Ryma, Sadowska, Justyna, Zehir, Ahmet, Syed, Aijazuddin, Wang, Yan Elsa, Somar, Joshua, Li, Yirong, Yelskaya, Zarina, Wong, Donna, Robson, Mark E, Offit, Kenneth, Berger, Michael F, Nafa, Khedoudja, Ladanyi, Marc, Zhang, Liying
Format:	Journal Article
Language:	English
Published:	England BioMed Central 19-05-2017 BMC
Subjects:	Adenomatous polyposis coli Adenomatous Polyposis Coli Protein - genetics Ataxia Telangiectasia Mutated Proteins - genetics Bioinformatics Biomarkers, Tumor - genetics BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Cancer Cancer Predisposition Checkpoint Kinase 2 - genetics Copy number Deoxyribonucleic acid DNA DNA Copy Number Variations DNA Mutational Analysis - methods Genes Genetic Predisposition to Disease Genetic testing Genomes Genomics Germ-Line Mutation Germline Mutation Haplotypes Hereditary Cancer Syndrome Humans Hybridization Laboratories Lynch Syndrome Mutation Neoplasm Proteins - genetics Neoplasms - genetics Neoplasms - metabolism p53 Protein Pathogenic Variant Polymorphism, Single Nucleotide Reproducibility of Results Technical Advance Tuberous Sclerosis Complex 2 Tumor Suppressor Protein p53 - genetics Tumor Suppressor Proteins - genetics VHL protein Von Hippel-Lindau Tumor Suppressor Protein - genetics
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Summary:	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.
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ISSN:	1755-8794 1755-8794
DOI:	10.1186/s12920-017-0271-4