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Frequent Alterations of the p14^ARF and p16^INK4a Genes in Primary Central Nervous System Lymphomas

Second Department of Pathology [M. N., E. I., K. S., N. K.] and Department of Neurosurgery [T. S., H. H., H. N.], Nara Medical University, 634-8521 Nara, Japan

To elucidate the role of p53/p16^INK4a/RB1 pathways in the tumorigenesis of primary central nervous system lymphomas (PCNSLs), we have analyzed p14^ARF, p16^INK4a, RB1, p21^Waf1, and p27^Kip1 status in a series of their 18 sporadic cases of diffuse large B-cell lymphoma, using methylation-specific PCR, differential PCR, and immunohistochemistry. Homozygous deletion or methylation of p14^ARF was detected in 10 (56%) PCNSLs, and they were almost entirely deletions (except 1 case). A total of 11 (61%) PCNSLs demonstrated homozygous deletion (6 cases) or methylation (5 cases) of p16^INK4a. Six tumors showed both p14^ARF and p16^INK4a homozygous deletions. Hypermethylation of the RB1 and the p27^Kip1 promoter region was detected in 2 (11%) cases, whereas p21^Waf1 methylation was not detected in any. Immunohistochemistry revealed loss of p14^ARF and p16^INK4a expression in 10 (56%) samples, correlating with the gene status. Four cases showed independent negative immunoreactivity for pRB and p27^Kip1, and nearly one-half of cases (8 of 18; 44%) were characterized by lack of p21^Waf1 expression. These results indicate that inactivation of p14^ARF and p16^INK4a by either homozygous deletion or promoter hypermethylation represents an important molecular pathogenesis in PCNSLs. Hypermethylation of RB1, p21^Waf1, and p27^Kip1 appears to be of minor significance, these genes being independently methylated in PCNSLs.

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