Deletions and loss of expression of p16(INK4a) and p21(Waf1) genes are associated with aggressive variants of mantle cell lymphomas

Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21(Waf1) and p16(INK4a) have been suggested as candidates for tumor-suppressor genes. To determine the role of p21(Waf1) and p16(INK4a) gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21(Waf1) and p16(INK4a) genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16(INK4a) expression. These cases showed homozygous deletions of p16(INK4a) gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21(Waf1) expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21(Waf1) gene deletions or mutations were found in this case. The p21(Waf1) expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21(Waf1) and p16(INK4a) expression whereas the 4 aggressive MCLs with p16(INK4a) and p21(Waf1) gene alterations had a wild-type p53. p21(Waf1) and p16(INK4a) were expressed at mRNA and protein levels in all typical MCLs examined. nio gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16(INK4a) gene and codon 31 of p21(Waf1) gene. These findings indicate that p21(Waf1) and p16(INK4a) alterations are rare in typical MCLs but the loss of p21(Waf1) and p16(INK4a) expression, and deletions of p16(INK4a) gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene. (C) 1997 by The American Society of Hematology.