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p16INK4a Gene Inactivation by Deletions, Mutations, and
Hypermethylation Is Associated With Transformed and Aggressive
Variants of Non-Hodgkin's Lymphomas
Magda Pinyol,
Francesc Cobo,
Silvia Bea,
Pedro Jares,
Iracema Nayach,
Pedro L. Fernandez,
Emilio Montserrat,
Antonio Cardesa, and
Elias Campo
From the Hematopathology Section, Laboratory of Pathology, and
Department of Hematology, Hospital Clinic, University of Barcelona,
Barcelona, Spain.
The molecular mechanisms underlying the pathogenesis of aggressive
lymphomas and the histological transformation of indolent variants are
not well known. To determine the role of p16INK4a gene
alterations in the pathogenesis of non-Hodgkin's lymphomas (NHLs) and
the histological progression of indolent variants, we have analyzed the
expression, deletions, and mutations of this gene in a series of 112 NHLs. Hypermethylation of the gene was also examined in a subset of
tumors with lack of protein expression but without mutations or
deletions of the gene. p16INK4a gene alterations were
detected in 3 out of 64 (5%) indolent lymphomas but in 16 out of 48 (33%) primary or transformed aggressive variants. In the low-grade
tumors, p16INK4a alterations were detected in 1 (4%)
chronic lymphocytic leukemia (hemizygous missense mutation), 1 (6%)
follicular lymphoma (homozygous deletion), and 1 (5%) typical mantle
cell lymphoma (homozygous deletion). The two later cases followed an
aggressive clinical evolution. In the aggressive tumors,
p16INK4a gene alterations were observed in 2 (29%)
Richter's syndromes (2 homozygous deletions), 3 (33%) transformed
follicular lymphomas (1 homozygous deletion and 2 nonsense mutations),
3 (43%) blastoid mantle cell lymphomas (2 homozygous and 1 hemizygous
deletions), 5 (28%) de novo large-cell lymphomas (1 homozygous
deletion and 4 hypermethylations), 2 lymphoblastic lymphomas (2 homozygous deletions), and 1 of 2 anaplastic large cell lymphomas
(hypermethylation). Protein expression was lost in all tumors with
p16INK4a alterations except in the typical chronic
lymphocytic leukemia (CLL) with hemizygous point mutation. Sequential
samples of the indolent and transformed phase of three cases showed the
presence of p16INK4a deletions in the Richter's syndrome
but not in the CLL component of two cases, whereas in a follicular
lymphoma the deletion was present in both the follicular tumor and in
the diffuse large-cell lymphoma. In conclusion, these findings indicate
that p16INK4a gene alterations are a relatively infrequent
phenomenon in NHLs. However, deletions, mutations, and hypermethylation
of the gene with loss of protein expression are associated with
aggressive tumors and they may also participate in the histological
progression of indolent lymphomas.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2977-2984
© 1998 by The American Society of Hematology.
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