Cited by 175BRCA gene mutations in cancerGenomics and Rare DiseasesCancer Genomics and Diagnostics

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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Cheng, Donavan T., Prasad, Meera, Chekaluk, Yvonne, Benayed, Ryma, Sadowska, Justyna, Zehir, Ahmet, Syed, Aijazuddin, Wang, Yan Elsa +10 more·2017·BMC Medical Genomics

Abstract

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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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  • MSK-IMPACT is an NGS assay that can detect variants in up to 505 unique cancer genes, including EGFR, TP53, KRAS, STK11, and ALK.

    “MSK-IMPACT is an NGS assay that can detect variants in up to 505 unique cancer genes, including EGFR, TP53, KRAS, STK11, and ALK.”

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Authors
Cheng, D. T., Prasad, M., Chekaluk, Y., Benayed, R., Sadowska, J., Zehir, A., Syed, A., Wang, Y. E., Somar, J., Li, Y., Yelskaya, Z., Wong, D., Robson, M. E., Offit, K., Berger, M. F., Nafa, K., Ladanyi, M., & Zhang, L.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Ladanyi, Marc
  • Zhang, Liying
Venue
BMC Medical Genomics
Published
2017-05-19
Volume
10
Issue
1
Pages
33-33
ISSN
1755-8794 (ISSN-L)
OpenAlex
W2614654783
Cited by
158
References
21
Citations by year
2026: 9 · 2025: 19 · 2024: 12 · 2023: 23 · 2022: 21 · 2021: 20 · 2020: 22 · 2019: 16 · 2018: 13 · 2017: 2
FWCI
9.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Medical Genomics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
  • Geoffrey Beene Cancer Research Center (P30 CA008748)
  • Farmer Family Foundation
  • National Cancer Institute (P30CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
MSK-IMPACT, germline variant detection, cancer predisposition syndromes, cancer susceptibility genes, gene panel testing, founder mutation, BRCA1, BRCA2, CHEK2, APC, TP53, TSC2, ATM, VHL, copy number variation, single nucleotide variants, hereditary cancer
MeSH terms
Tuberous Sclerosis Complex 2 Protein, DNA Mutational Analysis, Humans, Neoplasm Proteins, Neoplasms, Biomarkers, Tumor, Reproducibility of Results, Tumor Suppressor Protein p53, Germ-Line Mutation, BRCA1 Protein, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, BRCA2 Protein, Tumor Suppressor Proteins, Adenomatous Polyposis Coli Protein, Von Hippel-Lindau Tumor Suppressor Protein, DNA Copy Number Variations, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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