Differential effect of epigenetic alterations and genomic deletions of CDK inhibitors [p16(INK4a), p15(INK4b), p14(ARF)] in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in overexpression of CCND1 in the vast majority of cases. In addition, alterations of other cell-cycle-regulating signal pathways (CDKN2B/CDKN2A-CCND1 and ARF-MDM2-TP53) are frequently observed. However, the hierarchy of promoter methylations and genomic alterations as well as the interaction with other cell-cycle regulator CDKN1A is poorly understood. A complete methylation-specific PCR coupled with direct sequencing of 71 MCL patient samples previously characterized for TP53 alterations, Ki67 expression by immunohistochemistry, and other genomic alterations was performed. In contrast to rare p16(INK4a) promoter methylation (9%), frequent p15(INK4b) (62%) and p14(ARF) (70%) promoter methylation was detectable in MCL. In an additional 16% of MCL cases, LOH for p16(INK4a) was detected. However, MCL cases with p15(INK4b) methylation tended to have lower proliferation (73% vs. 57%), and p15(INK4b) and p14(ARF) promoter methylation was also detected in normal stem cells. Therefore, epigenetic changes of those genes seem not to represent primary oncogenic mechanisms but physiological mechanisms of cell regulation. The rare p16(INK4a) promoter methylation and p16(INK4a) genetic alterations were directly correlated to cell proliferation and therefore are regarded as additional molecular alterations involved in the cell-cycle dysregulation of MCL.