Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

Sergey I. Nikolaev, Donata Rimoldi, Christian Iseli, Armand Valsesia, Daniel Robyr, Corinne Gehrig, Keith Harshman, Michel Guipponi, Olesya Bukach, Vincent Zoete, Olivier Michielin, Katja Muehlethaler, Daniel Speiser, Jacques S. Beckmann, Ioannis Xenarios, Thanos D. Halazonetis, C. Victor Jongeneel, Brian J. Stevenson, Stylianos E. Antonarakis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)133-139
Number of pages7
JournalNature Genetics
Volume44
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Genetics

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