Loss of P16/INK4A Protein Expression in Non-Hodgkin's Lymphomas is a Frequent Finding Associated with Tumor Progression

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 1998 Sep 15

PMID 9736037

Citations 20

Authors

R Villuendas

M Sanchez-Beato

J C Martinez

A I Saez

B Martinez-Delgado

J F Garcia

M S Mateo

L Sanchez-Verde

J Benitez

P Martinez

M A Piris

Affiliations

Soon will be listed here.

Abstract

The CDKN2A gene located on chromosome region 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16/INK4A, a negative cell cycle regulator. We analyzed p16/INK4A expression in different types of non-Hodgkin's lymphoma to determine whether the absence of this protein is involved in lymphomagenesis, while also trying to characterize the genetic events underlying this p16/INK4A loss. To this end, we investigated the levels of p16/INK4A protein using immunohistochemical techniques in 153 cases of non-Hodgkin's lymphoma, using as reference the levels found in reactive lymphoid tissue. The existence of gene mutation, CpG island methylation, and allelic loss were investigated in a subset of 26 cases, using single-strand conformational polymorphism and direct sequencing, Southern Blot, polymerase chain reaction, and microsatellite analysis, respectively. Loss of p16/INK4A expression was detected in 41 of the 112 non-Hodgkin's lymphomas studied (37%), all of which corresponded to high-grade tumors. This loss of p16/INK4A was found more frequently in cases showing tumor progression from mucosa-associated lymphoid tissue low-grade lymphomas (31 of 37) or follicular lymphomas (4 of 4) into diffuse large B-cell lymphomas. Analysis of the status of the p16/INK4A gene showed different genetic alterations (methylation of the 5'-CpG island of the p16/INK4A gene, 6 of 23 cases; allelic loss at 9p21, 3 of 16 cases; and nonsense mutation, 1 of 26 cases). In all cases, these events were associated with loss of the p16/INK4A protein. No case that preserved protein expression contained any genetic change. Our results demonstrate that p16/INK4A loss of expression contributes to tumor progression in lymphomas. The most frequent genetic alterations found were 5'-CpG island methylation and allelic loss.

Citing Articles

Plasma DNA methylation of p16 and shp1 in patients with B cell non-Hodgkin lymphoma.

Ding K, Chen X, Wang Y, Liu H, Song W, Li L Int J Clin Oncol. 2017; 22(3):585-592.

PMID: 28210822 DOI: 10.1007/s10147-017-1100-7.

Loss of P16 Protein Expression and Its Association with Epstein-Barr Virus LMP-1 Expression in Hodgkin's Lymphoma.

Irshaid F, Tarawneh K, Alshdefat A, Dilmi F, Jaran A, Al-Hadithi R Iran J Cancer Prev. 2014; 6(2):78-84.

PMID: 25250115 PMC: 4142916.

The p53 Mutation/Deletion Profile in a Small Cohort of the Omani Population with Diffuse Large B-Cell Lymphoma.

Tamimi Y, Al-Harthy S, Al-Haddabi I, Al-Kindi M, Babiker H, Al-MoundhrI M Sultan Qaboos Univ Med J. 2014; 14(1):e50-8.

PMID: 24516754 PMC: 3916277. DOI: 10.12816/0003336.

Colorectal cancer DNA methylation marker panel validated with high performance in Non-Hodgkin lymphoma.

Bethge N, Lothe R, Honne H, Andresen K, Troen G, Eknaes M Epigenetics. 2013; 9(3):428-36.

PMID: 24362313 PMC: 4053461. DOI: 10.4161/epi.27554.

Prognostic significance of epigenetic inactivation of p16, p15, MGMT and DAPK genes in follicular lymphoma.

Krajnovic M, Radojkovic M, Davidovic R, Dimitrijevic B, Krtolica K Med Oncol. 2013; 30(1):441.

PMID: 23275143 DOI: 10.1007/s12032-012-0441-3.

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