Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

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

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Title		Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma
Authors		Nikolaev, Sergey Igorievich Rimoldi, Donata Iseli, Christian Valsesia, Armand Robyr, Daniel Gehrig, Corinne Harshman, Keith Guipponi, Michel Bukach, Olesya Zoete, Vincent Michielin, Olivier Muehlethaler, Katja Speiser, Daniel Beckmann, Jacques S Xenarios, Ioannis Halazonetis, Thanos Jongeneel, C Victor Stevenson, Brian J Antonarakis, Stylianos show all authors [1 - 19]
Published in		Nature Genetics. 2012, vol. 44, no. 2, p. 133-9
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.
Keywords		Base Sequence — Cadherins/genetics — Cell Line, Tumor — Cohort Studies — DNA Repair/genetics — Desmocollins — Exome/genetics — Humans — MAP Kinase Kinase 1/antagonists & inhibitors/genetics — MAP Kinase Kinase 2/antagonists & inhibitors/genetics — Melanoma/genetics — Mitogen-Activated Protein Kinase 1/genetics — Molecular Sequence Data — Mutation — Proto-Oncogene Proteins B-raf/genetics — Receptors, LDL/genetics — Skin Neoplasms/genetics — Tumor Suppressor Proteins/genetics — Ultraviolet Rays/adverse effects
Identifiers		DOI: 10.1038/ng.1026 PMID: 22197931
Full text		Article (Published version) (806 Kb) - Limited access to UNIGE
Structures		Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté des sciences / Section de biologie / Département de biologie moléculaire
Research group		Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
Citation (ISO format)		NIKOLAEV, Sergey Igorievich et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. In: Nature Genetics, 2012, vol. 44, n° 2, p. 133-9. https://archive-ouverte.unige.ch/unige:34654