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

Brain Pathology - Tập 8 Số 2 - Trang 263-276 - 1998
J. M. J. Ludwig Cobbers1,2, Marietta Wolter1,2, Julia Reifenberger3,2, Gudrun U. Ring1, Frank Jessen1, Han‐Xiang An4,5, Dieter Niederacher4,5, Esther Schmidt6, Koichi Ichimura6, Frank Floeth7, Lutz Kirsch8, F Borchard9, David N. Louis10, Collins Vp6, Guido Reifenberger4,1
1Departments of Neuropathology, Heinrich-Heine-Universität, Düsseldorf, Germany
2These authors contributed equally to the work
3Dermatology, Heinrich-Heine-Universität, Düsseldorf, Germany
4Center for Biological and Medical Research (BMFZ) 6 , Heinrich-Heine-Universität, Düsseldorf, Germany
5Gynecology, Heinrich-Heine-Universität, Düsseldorf, Germany
6Institute for Oncology and Pathology, Division of Tumor Pathology, and Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Hospital, Stockholm, Sweden
7Neurosurgery, Heinrich-Heine-Universität, Düsseldorf, Germany
8Neurosurgical Clinic, Evangelische-und-Johanniter-Krankenanstalten Duisburg-Nord/Oberhausen, Germany
9Pathology, Heinrich-Heine-Universität, Düsseldorf, Germany
10Molecular Neuro-Oncology Laboratory, Department of Pathology (Neuropathology) and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Tóm tắt

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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Brain Pathology

Tập 8 Số 2

263-276

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