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Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing
Open accessAbstract
As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.
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“Targeted multiplexed hotspot panels (e.g., Agena Oncocarta [Agena Bioscience, San Diego, CA], 47 SNaPshot [Applied Biosystems, Foster City, CA], 48 and next-generation sequencing [NGS] panels 49,50 ) have already been developed and are available in College of American Pathologists (CAP)-accredited academic and commercial laboratories.”
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“CGP was performed using the FoundationOne assay (Cambridge, MA, USA), as previously described in detail [55, 56].”
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“The methods have been previously described (20).”
Metadata
- Authors
- Frampton, G. M., Fichtenholtz, A., Otto, G. A., Wang, K., Downing, S. R., He, J., Schnall-Levin, M., White, J., Sanford, E. M., An, P., Sun, J., Juhn, F., Brennan, K., Iwanik, K., Maillet, A., Buell, J., White, E., Zhao, M., Balasubramanian, S., Terzic, S., Richards, T., Banning, V., Garcia, L., Mahoney, K., Zwirko, Z., Donahue, A., Beltran, H., Mosquera, J. M., Rubin, M. A., Dogan, S., Hedvat, C. V., Berger, M. F., Pusztai, L., Lechner, M., Boshoff, C., Jarosz, M., Vietz, C., Parker, A., Miller, V. A., Ross, J. S., Curran, J., Cronin, M. T., Stephens, P. J., Lipson, D., & Yelensky, R.
- Affiliations
- Foundation Medicine (United States) (US)
- NewYork–Presbyterian Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Yale Cancer Center (US)
- University College London (GB)
- Corresponding author
- Lipson, Doron
- Yelensky, Roman
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2013-11
- Volume
- 31
- Issue
- 11
- Pages
- 1023-1031
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5710001
- OpenAlex
- W2160981405
- Cited by
- 2,157
- References
- 54
- Citations by year
- 2026: 91 · 2025: 122 · 2024: 139 · 2023: 215 · 2022: 208 · 2021: 188 · 2020: 213 · 2019: 185 · 2018: 195 · 2017: 180 · 2016: 182 · 2015: 159 · 2014: 76 · 2013: 2
- FWCI
- 49.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (WT093855MA)
- National Cancer Institute (P30CA008748)
- 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
- tumor genomic profiling, analytical method validation, formalin-fixed paraffin-embedded tissue, copy number alterations, indels, gene fusion, actionable mutations, mutant allele frequency, sensitivity and specificity, precision oncology
- MeSH terms
- DNA Mutational Analysis, Gene Frequency, Humans, Neoplasms, Sensitivity and Specificity, Reproducibility of Results, Sequence Analysis, DNA, Molecular Diagnostic Techniques, DNA Copy Number Variations
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