Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation.
We have addressed whether aberrant ongoing hypermutation can be detected in the proto-oncogenes PIM1, c-MYC, RhoH/TTF, PAX5, and the tumor-suppressor gene CD95 in primary central nervous system lymphomas (PCNSLs) derived from immunocompetent HIV-negative patients. Nine of 10 PCNSLs analyzed harbored somatic mutations in the PIM1, c-MYC, RhoH/TTF, and PAX5 genes, but not in the CD95 gene, with 8 tumors carrying alterations in at least 2 of these genes. Furthermore, ongoing aberrant mutation was evidenced in a subset of PCNSLs (2 of 3). Although most of the mutations corresponded to base pair substitutions, deletions were also present. The mean mutation frequency was approximately 60-fold lower for these genes compared with the values obtained for immunoglobulin genes in PCNSL. They were increased 2- to 5-fold compared with extracerebral diffuse large B-cell lymphoma (DLBCL). In summary, our data demonstrate aberrant somatic hypermutations at high frequency in the PIM1, PAX5, RhoH/TTF, and c-MYC genes in most PCNSLs. These findings may indicate a pathogenic role for aberrant somatic hypermutation in PCNSL development. In contrast, although mutations were detected in exon 9 of the CD95 gene, the lack of mutations in the 5' region provides no evidence for the CD95 gene as a target for aberrant somatic mutation.
Department of Neuropathology, University of Cologne, Köln, Germany.
Manuel
M
Montesinos-Rongen
Dirk
D
Van Roost
Carlo
C
Schaller
Otmar D
OD
Wiestler
Martina
M
Deckert
D016543:Central Nervous System Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D015321:Gene Rearrangement; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009154:Mutation; D051757:PAX5 Transcription Factor; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D019014:fas Receptor / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C447841:RhoH protein, human; D014157:Transcription Factors; D019014:fas Receptor; D012697:Serine Endopeptidases; D020741:rho GTP-Binding Proteins