Frequent methylation silencing of p15(INK4b) (MTS2) and p16(INK4a) (MTS1) in B-cell and T-cell lymphomas

The methylation status of p15(INK4b) (MTS2), p16(IK4a) (MTS1) and p14(ARF) (p16 beta) was analyzed in 56 lymphomas by restriction-enzyme related polym erase chain reaction (PCR) (REF), methylation-specific PCR (MSP), and bisul fite genomic sequencing (BGS). Methylation of the p15 and p16 genes was det ected, respectively, in 64% and 32% of the B-cell lymphomas, in 44% and 22% of the T-cell lymphomas, and in none of the 5 reactive lymph nodes analyze d. Both p75 and p16 genes were methylated more often in the high-grade (78% and 50%, respectively) than in the low-grade B-cell lymphomas (55% and 21% , respectively). For 5 cases, mapping of the methylated CpGs of the p16 pro moter region confirmed the results of REP and MSP. In addition, a large var iation in the methylation patterns of p16 exon 1 was observed, not only fro m one lymphoma to another, but also within a given tumor. Methylation of p1 5 and p16 was associated with an absence of gene expression, as assessed by reverse transcription-PCR. The p14 gene was unmethylated and normally expr essed in all 56 tumors. We found no mutations of p75, p16, or p14 in any of the 56 lymphomas. Our results suggest a role for p15 and p16 gene methylat ion during lymphomagenesis and a possible association between p15 and p16 i nactivation and aggressive transformation in B-cell and T-cell lymphomas. ( C) 1999 by The American Society of Hematology.