title: Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Christian
authors.initials: C
authors.lastname: Iseli
authors.forename: Armand
authors.initials: A
authors.lastname: Valsesia
authors.forename: Daniel
authors.initials: D
authors.lastname: Robyr
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.forename: Keith
authors.initials: K
authors.lastname: Harshman
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Olesya
authors.initials: O
authors.lastname: Bukach
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Katja
authors.initials: K
authors.lastname: Muehlethaler
authors.forename: Daniel
authors.initials: D
authors.lastname: Speiser
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
authors.forename: C Victor
authors.initials: CV
authors.lastname: Jongeneel
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D001483:Base Sequence; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics; D051187:Desmocollins; D059472:Exome / Q000235:genetics*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D015820:Cadherins; C081560:DSC1 protein, human; D051187:Desmocollins; C534294:FAT4 protein, human; C434476:LRP1B protein, human; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human