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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1869-1875.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-05-1465.
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NEOPLASIA
Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation
Manuel Montesinos-Rongen,
Dirk Van Roost,
Carlo Schaller,
Otmar D. Wiestler, and
Martina Deckert
From the Department of Neuropathology, University of Cologne, and the Departments of Neuropathology and Neurosurgery, University of Bonn, Germany.
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.
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