Abstract
We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Cadherins / genetics
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Cell Line, Tumor
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Cohort Studies
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DNA Repair / genetics
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Desmocollins
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Exome / genetics*
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / genetics*
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MAP Kinase Kinase 2 / antagonists & inhibitors
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MAP Kinase Kinase 2 / genetics*
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Melanoma / genetics*
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Mitogen-Activated Protein Kinase 1 / genetics*
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Molecular Sequence Data
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Mutation*
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Proto-Oncogene Proteins B-raf / genetics
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Receptors, LDL / genetics
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Skin Neoplasms / genetics*
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Tumor Suppressor Proteins / genetics
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Ultraviolet Rays / adverse effects
Substances
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Cadherins
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DSC1 protein, human
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Desmocollins
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FAT4 protein, human
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LRP1B protein, human
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Receptors, LDL
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Tumor Suppressor Proteins
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MAP2K2 protein, human
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human