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(American Journal of Pathology. 2000;156:1565-1572.)
© 2000 American Society for Investigative Pathology

Regular Articles

p16^INK4a Gene Alterations Are Frequent in Lesions of Mycosis Fungoides

Inmaculada C. Navas^*, Pablo L. Ortiz-Romero, Raquel Villuendas^*, Pedro Martínez^*, Carmen García, Enrique Gómez, Jose L. Rodriguez^§, Domingo García, Francisco Vanaclocha, Luis Iglesias, Miguel A. Piris^¶ and Patrocinio Algara^*

From the Departments of Genetics,^*
Dermatology,
and Pathology,^¶
Virgen de la Salud Hospital, Toledo; and the Departments of Dermatology
and Pathology,^§
12 de Octubre Hospital, Madrid, Spain

Mycosis fungoides is usually an indolent disease that, after a variable period of time in a stable phase, evolves into a tumoral form with aggressive behavior. The molecular events that mark this progression remain essentially unknown to date, and this prompted us to investigate the hypothetical role of p16^INK4a silencing in mycosis fungoides progression. We analyzed the three most frequent mechanisms of inactivation of the p16^INK4a gene (deletion, promoter hypermethylation, and mutation) in nine cases with patch/plaque and tumoral lesions of mycosis fungoides. The existence of alterations was investigated by microsatellite analysis, methylation-specific polymerase chain reaction, and direct sequencing. Alterations of the p16^INK4a gene were found in four of nine of the plaque lesions (hypermethylation in three samples and allelic loss in one sample) and seven of nine in the tumor lesions (hypermethylation in five samples and allelic loss in three samples). No case presented point mutations. Although a higher incidence of p16^INK4a hypermethylation was observed in the cases that failed to achieve a complete remission, the limited size of our series prompted us to evaluate this finding cautiously. The results of this study therefore showed a common genetic alteration that is found more frequently in tumoral lesions than it is in plaque lesions of mycosis fungoides. It also offers data that could suggest a relationship between p16^INK4a hypermethylation and unfavorable clinical outcome. Broader studies are needed to confirm both relationships.

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