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. 2006 Apr 5;8(2):263–276. doi: 10.1111/j.1750-3639.1998.tb00152.x

Frequent In activation of CDKN2A and Rare Mutation of TP53 in PCNSL

JMJ Ludwig Cobbers 1,*, Marietta Wolter 1,*, Julia Reifenberger 2,*, Gudrun U Ring 1, Frank Jessen 1, Han‐Xiang An 3,6, Dieter Niederacher 3,6, Esther E Schmidt 8, Koichi Ichimura 8, Frank Floeth 4, Lutz Kirsch 7, Franz Borchard 5, David N Louis 9, V Peter Collins 8, Guido Reifenberger 1,6,✉
PMCID: PMC8098352  PMID: 9546285

Abstract

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B‐cell lymphomas and one T‐cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG: Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl‐2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.

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