Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma |
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Authors: | William R. Jeck Joel Parker Craig C. Carson Janiel M. Shields Maria J. Sambade Eldon C. Peters Christin E. Burd Nancy E. Thomas Derek Y. Chiang Wenjin Liu David A. Eberhard David Ollila Juneko Grilley‐Olson Stergios Moschos D. Neil Hayes Norman E. Sharpless |
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Affiliation: | 1. Department of Genetics, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;2. The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;3. Department of Dermatology, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;4. Department of Radiation Oncology, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;5. Department of Medicine, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;6. Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, , Chapel Hill, NC, USA;7. Department of Surgery, University of North Carolina School of Medicine, , Chapel Hill, NC, USA |
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Abstract: | Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high‐throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard‐of‐care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma. |
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Keywords: | genomics therapeutics clinical trials diagnostics resequencing |
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