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(American Journal of Pathology. 2000;156:1987-1996.)
© 2000 American Society for Investigative Pathology

Regular Articles

INK4a/ARF Locus Alterations in Human Non-Hodgkin’s Lymphomas Mainly Occur in Tumors with Wild-Type p53 Gene

Magda Pinyol*, Luis Hernández*, Antonio Martínez*, Francesc Cobo{dagger}, Silvia Hernández*, Silvia Beà*, Armando López-Guillermo{dagger}, Iracema Nayach*, Antonio Palacín*, Alfons Nadal*, Pedro L. Fernández*, Emilio Montserrat{dagger}, Antonio Cardesa* and Elías Campo*

From the Laboratory of Pathology*
and Department of Hematology,{dagger}
Hospital Clínic, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

INK4a/ARF locus codes for two different proteins, p16INK4a and p14ARF, involved in cell cycle regulation. p14ARF is considered an upstream regulator of p53 function. To determine the role of these genes in the pathogenesis of human non-Hodgkin’s lymphomas we have analyzed exon 1ß, 1{alpha}, and 2 of the INK4a/ARF locus and p53 gene aberrations in 97 tumors previously characterized for p16INK4a alterations. p53 alterations were detected in four of 51 (8%) indolent lymphomas but in 15 of 46 (33%) aggressive tumors. Inactivation of p14ARF was always associated with p16INK4a alterations. Exon 1ß was concomitantly deleted with exon 1{alpha} and 2 in eight tumors. One additional lymphoblastic lymphoma showed deletion of exon 1{alpha} and 2 but retained exon 1ß. No mutations were detected in exon 1{alpha} and 1ß in any case. Two of the three mutations detected in exon 2 caused a nonsense mutation in the p16INK4a reading frame and a missense mutation in the ARF reading frame involving the nucleolar transport domain of the protein. The third mutation was a missense mutation in the p16INK4a reading frame, but it was outside the coding region of p14ARF. Aggressive lymphomas with p14ARF inactivation and p53 wild type showed a significantly lower p53 protein expression than tumors with no alteration in any of these genes. In this series of tumors, inactivation of the INK4a/ARF locus mainly occurred in tumors with a wild-type p53 gene because only two lymphomas showed simultaneous aberrations in these genes. Tumors with concomitant alterations of p16INK4a and p14ARF/p53 genes seem to exhibit a worse clinical behavior than lymphomas with no alterations or isolated inactivation of any of these genes. These findings indicate that p14ARF genetic alterations occur in a subset of aggressive NHLs, but they are always associated with p16INK4a aberrations. Concomitant disruption of p16INK4a and p14ARF/p53 regulatory pathways may have a cooperative effect in the progression of these tumors.




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