Cited by 2,119Cancer Genomics and DiagnosticsGenomics and Rare DiseasesBRCA gene mutations in cancer

Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)

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Cheng, Donavan T., Mitchell, Talia N., Zehir, Ahmet, Shah, Ronak H., Benayed, Ryma, Syed, Aijazuddin, Chandramohan, Raghu, Liu, Zhen Yu +19 more·2015·The Journal of Molecular Diagnostics

Abstract

The identification of specific genetic alterations as key oncogenic drivers and the development of targeted therapies are together transforming clinical oncology and creating a pressing need for increased breadth and throughput of clinical genotyping. Next-generation sequencing assays allow the efficient and unbiased detection of clinically actionable mutations. To enable precision oncology in patients with solid tumors, we developed Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 341 key cancer genes in formalin-fixed, paraffin-embedded tumors. Barcoded libraries from patient-matched tumor and normal samples were captured, sequenced, and subjected to a custom analysis pipeline to identify somatic mutations. Sensitivity, specificity, reproducibility of MSK-IMPACT were assessed through extensive analytical validation. We tested 284 tumor samples with previously known point mutations and insertions/deletions in 47 exons of 19 cancer genes. All known variants were accurately detected, and there was high reproducibility of inter- and intrarun replicates. The detection limit for low-frequency variants was approximately 2% for hotspot mutations and 5% for nonhotspot mutations. Copy number alterations and structural rearrangements were also reliably detected. MSK-IMPACT profiles oncogenic DNA alterations in clinical solid tumor samples with high accuracy and sensitivity. Paired analysis of tumors and patient-matched normal samples enables unambiguous detection of somatic mutations to guide treatment decisions.

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  • Exome sequencing of sorted cKit+ Lymph- Ery- HSPCs and paired tail tissue using the MSK-IMPACT mouse panel of 578 cancer-related genes showed evidence for expansion of clonal cell populations in all leukemic compound mutant mice tested.

    “Exome sequencing of sorted cKit+ Lymph– Ery– HSPCs and paired tail tissue specimen using the Memorial Sloan Kettering Cancer Center's Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) mouse panel of 578 cancer-related genes (31) showed evidence for expansion of clonal cell populations in all leukemic compound mutant mice tested (Supplementary Tables S2 and S3).”

    From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [31]

    The Panel Design and Target Region Coverage section identifies MSK-IMPACT as a targeted sequencing assay for cancer-related genes, supporting the citation's identification of the method. It describes a 341-gene panel, however, not a 578-gene mouse panel. The cited paper does not report the mouse HSPC sequencing or clonal-expansion result; the citing sentence points to its own supplementary tables for that result. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR: The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet 2008. Chapter 10:Unit 10.11
  2. Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010, 38:e164

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Authors
Cheng, D. T., Mitchell, T. N., Zehir, A., Shah, R. H., Benayed, R., Syed, A., Chandramohan, R., Liu, Z. Y., Won, H. H., Scott, S. N., Brannon, A. R., O'Reilly, C., Sadowska, J., Casanova, J., Yannes, A., Hechtman, J. F., Yao, J., Song, W., Ross, D. S., Oultache, A., Dogan, S., Borsu, L., Hameed, M., Nafa, K., Arcila, M. E., Ladanyi, M., & Berger, M. F.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Berger, Michael F.
Venue
The Journal of Molecular Diagnostics
Publisher
Elsevier BV
Published
2015-05
Volume
17
Issue
3
Pages
251-264
ISSN
1525-1578 (ISSN-L)
OpenAlex
W223909586
Cited by
2,119
References
8
Citations by year
2026: 139 · 2025: 225 · 2024: 246 · 2023: 188 · 2022: 252 · 2021: 240 · 2020: 231 · 2019: 176 · 2018: 151 · 2017: 126 · 2016: 101 · 2015: 40 · 2014: 3
FWCI
46.08
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular Diagnostics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Department of Pathology, Memorial Sloan Kettering Cancer Center
  • Farmer Family Foundation
  • Geoffrey Beene Cancer Research Center
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Keywords
MSK-IMPACT, somatic mutations, hybridization capture sequencing, precision oncology, solid tumors, formalin-fixed paraffin-embedded tissue, targeted deep sequencing, copy number alterations, structural rearrangement, low-frequency variant detection, analytical method validation, targeted therapy
MeSH terms
DNA, DNA Mutational Analysis, Genotype, Humans, Mutation, Neoplasms, Reproducibility of Results, Paraffin Embedding, High-Throughput Nucleotide Sequencing

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