Mutations of BRAF and RAS are rare events in germ cell tumours.
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.
Sommerer
Florian
F
Institute of Pathology, University of Leipzig, Liebigstrasse 26, D-04103 Leipzig, Germany.
Hengge
Ulrich R
UR
Markwarth
Annett
A
Vomschloss
Susanne
S
Stolzenburg
Jens-Uwe
JU
Wittekind
Christian
C
Tannapfel
Andrea
A
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
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf