title: Mutations of BRAF and RAS are rare events in germ cell tumours.
abstract: The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Recently, somatic missense mutations in the BRAF gene have been detected in a variety of human tumors. We have studied male germ cell tumours (GCT) for probable mutations of the BRAF and Ras oncogene. Microsatellite instability (MSI) was analysed using mono- or di-nucleotide marker. Mutational analysis of 62 GCT (30 seminomas and 32 nonseminomas) was performed after microdissection of the different tumour components. The expression of Erk1/2, an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway was assessed immunohistochemically. Activating BRAF missense mutations were identified in 3 out of 32 cases of nonseminomas (9%) but not in seminomas. The mutations were 1796T>A mutations and were found within the embryonic carcinoma component of these tumors. Two out of 30 seminomas (7%) and 3 out of 32 nonseminomas (9%) exhibited KRAS gene mutations. MSI was observed in 4 out 62 tumours (7%) [1 seminoma and 3 nonseminomas (embryonal carcinoma)]. All of the microsatellite instable embryonal carcinomas had a mutated BRAF gene. All 5 GCT with RAS mutations had an intact BRAF gene. We identified constitutively activated Erk in almost all tumours tested. Our data indicate that BRAF gene mutations are a rare event in GCT and are independent of KRAS mutations. In embryonal carcinomas, BRAF mutations may be linked to the proficiency of these tumours in repairing mismatched bases in DNA. The finding of activated Erk suggests a causative role for MAPK activation in GCT independent of activating BRAF or RAS mutations.
authors.affiliation: Institute of Pathology, University of Leipzig, Liebigstrasse 26, D-04103 Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Sommerer
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Hengge
authors.forename: Annett
authors.initials: A
authors.lastname: Markwarth
authors.forename: Susanne
authors.initials: S
authors.lastname: Vomschloss
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Stolzenburg
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
mesh_terms: D004252:DNA Mutational Analysis; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D018239:Seminoma / Q000235:genetics* / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf