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Deletions and loss of expression of p16INK4a and p21Waf1 genes are
associated with aggressive variants of mantle cell lymphomas
M Pinyol, L Hernandez, M Cazorla, M Balbin, P Jares, PL Fernandez, E Montserrat, A Cardesa, C Lopez-Otin and E Campo
Department of Anatomic Pathology, Hospital Clinic Provincial, University of
Barcelona, Spain.
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) p21Waf1 and p16INK4a have been suggested as candidates
for tumor-suppressor genes. To determine the role of p21Waf1 and p16INK4a
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 p21Waf1 and
p16INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the
typical variants. Two aggressive MCLs showed a loss of p16INK4a expression.
These cases showed homozygous deletions of p16INK4a gene by Southern blot
analysis. An additional aggressive MCL in which expression could not be
examined showed a hemizygous 9p12 deletion. Loss of p21Waf1 expression at
both protein and mRNA levels was detected in an additional aggressive MCL.
No p21Waf1 gene deletions or mutations were found in this case. The p21Waf1
expression in MCLs was independent of p53 mutations. The two cases with p53
mutations showed p21Waf1 and p16INK4a expression whereas the 4 aggressive
MCLs with p16INK4a and p21Waf1 gene alterations had a wild-type p53.
p21Waf1 and p16INK4a were expressed at mRNA and protein levels in all
typical MCLs examined. No 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 p16INK4a gene and codon 31 of p21Waf1 gene. These findings indicate
that p21Waf1 and p16INK4a alterations are rare in typical MCLs but the loss
of p21Waf1 and p16INK4a expression, and deletions of p16INK4a gene are
associated with aggressive variants of MCLs, and they occur in a subset of
tumors with a wild-type p53 gene.
Volume 89,
Issue 1,
pp. 272-280,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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