NATURE GENETICS VOLUME 44 | NUMBER 2 | FEBRUARY 2012 133 ARTICLES Malignant melanoma, a highly aggressive form of cancer that is mostly resistant to conventional chemotherapy, causes 75% of deaths related to skin cancer, with an estimated total of 48,000 fatalities worldwide per year 1 . The major environmental risk factor for cutaneous melanoma is UV exposure. Over 80% of cutaneous melanomas, particularly those arising on skin sites intermittently exposed to sun, harbor mutually exclusive activating mutations in the BRAF and NRAS genes 2,3 . These mutations are early events in melanocytic transformation. The BRAF mutation encoding p.Val600Glu accounts for 95% of all BRAF muta- tions found in melanomas 4 . A melanoma genome was among the first cancer genomes to be sequenced 5 , and a recent sequencing of melanoma exomes has iden- tified frequent mutations in TRRAP and GRIN2A (ref. 6). In order to reveal additional driver mutations as well as mutations potentially facilitating tumor progression, we performed exome sequencing of seven metastases from sporadic cases of cutaneous melanoma (and donor-matched germline cells), in one instance including two distinct metastases from the same individual. RESULTS Spectrum and type of somatic mutations in melanoma In seven melanoma exomes, we detected a total of 4,933 somatic variants, 3,611 of which were located in protein-coding regions in 2,586 affected genes (Supplementary Table 1). The background muta- tion rate varied greatly between melanomas and ranged from 6.4 to 49.9 mutations per million base pairs. Between 178 and 1,296 somatic alterations were detected in each melanoma, of which 104–761 were missense mutations, 4–49 were nonsense mutations, 0–10 affected splice sites and 3–7 were short insertions and/or deletions (indels) in the coding regions (Fig. 1a and Supplementary Fig. 1). The number of mutations across the samples was independent of disease stage (for example, regional versus distant metastasis; Supplementary Table 1), suggesting that a given mutation load may be characteristic of particular individuals or lesions. In all seven melanomas, C>T/G>A transitions dominated the mutational spectrum (73–87% of all mutations) (Fig. 1b). Of the C>T mutations, 84–91% occurred at the 3′ end of a pyrimidine dinucleo- tide sequence, which was significantly more than the 53% expected to be localized to these sites by chance (P < 1.26 × 10 –18 ). The preva- lence of such mutations is indicative of the repair of UV-induced damage by the nucleotide-excision repair (NER) system and transle- sional synthesis (TLS) polymerases 7,8 . In addition, CC>TT/GG>AA changes, which are also signatures of UV-induced damage, accounted for 50–87% of all somatic dinucleotide changes. This mutation spec- trum is consistent with tumors arising in sun-exposed skin sites. C>A/ G>T transversions, which can result from oxidative damage, were the Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma Sergey I Nikolaev 1,13 , Donata Rimoldi 2,13 , Christian Iseli 2,3,13 , Armand Valsesia 2–4 , Daniel Robyr 1 , Corinne Gehrig 1 , Keith Harshman 5 , Michel Guipponi 1 , Olesya Bukach 6 , Vincent Zoete 3 , Olivier Michielin 2,3,7 , Katja Muehlethaler 2 , Daniel Speiser 2 , Jacques S Beckmann 4,8 , Ioannis Xenarios 3 , Thanos D Halazonetis 9 , C Victor Jongeneel 2,3,10,11 , Brian J Stevenson 2,3 & Stylianos E Antonarakis 1,12 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. 1 Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. 2 Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. 3 Swiss Institute of Bioinformatics, Lausanne, Switzerland. 4 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. 5 Lausanne Genomic Technologies Facility, Center for Integrative Genomics, Lausanne, Switzerland. 6 Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland. 7 Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. 8 Service of Medical Genetics, CHUV, Lausanne, Switzerland. 9 Department of Molecular Biology, University of Geneva, Geneva, Switzerland. 10 National Center for Supercomputing Applications, University of Illinois, Urbana, Illinois, USA. 11 Institute for Genomic Biology, University of Illinois, Urbana, Illinois, USA. 12 Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland. 13 These authors contributed equally to this work. Correspondence should be addressed to S.I.N. (serg.nikolaev@gmail.com), D.R. (donata.rimoldi@unil.ch) or S.E.A. (Stylianos.Antonarakis@unige.ch). Received 17 May; accepted 4 November; published online 25 December 2011; doi:10.1038/ng.1026 npg © 2012 Nature America, Inc. All rights reserved.