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Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma
Author(s) -
Jeck William R.,
Parker Joel,
Carson Craig C.,
Shields Janiel M.,
Sambade Maria J.,
Peters Eldon C.,
Burd Christin E.,
Thomas Nancy E.,
Chiang Derek Y.,
Liu Wenjin,
Eberhard David A.,
Ollila David,
GrilleyOlson Juneko,
Moschos Stergios,
Neil Hayes D.,
Sharpless Norman E.
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12238
Subject(s) - pten , melanoma , cancer research , biology , cdkn2a , dna sequencing , mutation , computational biology , genetics , cancer , gene , pi3k/akt/mtor pathway , apoptosis
Summary 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 ERBB 4 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.