p16INK4a is selectively silenced in the tumoral progression of mycosis fungoides

Abstract

Knowledge about the molecular mechanisms involved in the pathogenesis of tumoral progression in mycosis fungoides (MF) is still scarce. Because the 9p21 locus seems to be a good target for a detailed study in MIF, this prompted us to compare the mechanisms of inactivation of the p16INK4a, p15INK4b, and p14ARF genes in aggressive and stable forms of MIF, performing microsatellite analysis, methylation-specific polymerase chain reaction, direct sequencing, and p16INK4a protein expression by immunohistochemistry. Additionally, the p53 gene was also sequenced in tumoral lesions. Thirty-nine patients with stable MF were studied. Alterations in p16INK4a and p15INK4b genes were detected in 18% and 5% of the cases, respectively. None of the cases analyzed showed alterations of the p14ARF gene. In contrast with these findings, in the 11 patients with aggressive MF, alterations of the p16INK4a, p15INK4b, or p14ARF genes were found in 8 (73%), 3 (27%), and 2 (18%) cases, respectively. A significant proportion (4/11) of these alterations were already present in the p16INK4a gene, in the initial plaque lesions in these aggressive forms of MF. Alterations in the p16INK4a gene, either methylation or loss of heterozygosity, were clearly more frequent than those in the p15INK4b and p14arf genes. The p16INK4a alterations were confirmed using immunohisto-chemistry. None of the nine tumoral lesions analyzed showed mutations in exons 1-2 of the p16INK4a gene or in exons 5-8 of the p53 gene. These results seem to suggest that 9p21 alterations, and selectively p16INK4a silencing, could be a characteristic phenomenon in MF progression.