title: Varying Mutational Alterations in Multiple Primary Melanomas.
abstract: In melanoma, the mitogen-activated protein (MAP) kinase pathway plays a crucial oncogenic role. Recent studies identified additional genetic alterations, eg, TERT-promoter mutations. Up to 8% of melanoma patients present with multiple primary melanomas (MPMs). The pathogenesis is not fully understood, and data on the genetic diversity of MPMs are limited. To identify putative diagnostic and therapeutic consequences, we assessed the mutational status of the BRAF and NRAS genes and TERT promoter in patients with MPMs. The study cohort consisted of 96 patients with 237 malignant melanomas. The BRAF, NRAS, and TERT-promoter genotypes were assessed in all MPMs and were correlated with patients' clinicopathological characteristics. BRAF mutations were found in 84 melanomas (35.4%), NRAS mutations, in 33 (14.0%); and TERT-promoter mutations, in 112 (47.3%). Mutation patterns were concordant between first and subsequent primary tumors in 23.9% of patients and were discordant in 61.4% of patients. The genetic alterations were partially different in 14.7% of patients. By Cox regression analysis, only the NRAS mutation had a significant negative prognostic impact on time to progression to stage III (P = 0.016) and on distant metastasis-free survival (P = 0.032). In the majority of primary melanomas in patients with MPMs, BRAF, NRAS, and TERT-promoter genotypes were discordant. Thus, molecular testing for targeted therapy should be performed on metastatic tissue and not on primary tumors.
authors.affiliation: Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany. Electronic address: fegberts@dermatology.uni-kiel.de.
authors.forename: Friederike
authors.initials: F
authors.lastname: Egberts
authors.affiliation: Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
authors.forename: Ann-Sophie
authors.initials: AS
authors.lastname: Bohne
authors.affiliation: Department of Pathology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Krüger
authors.affiliation: Department of Clinical Informatics and Statistics, University of Kiel, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hedderich
authors.affiliation: Department of Dermatology, Municipal Hospital Kassel, Kassel, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Rompel
authors.affiliation: Department of Pathology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Haag
authors.affiliation: Department of Pathology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Department of Dermatology, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods; D009154:Mutation / Q000235:genetics; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D019098:Telomerase / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human