Methylation of p15 and p16 genes in adult acute leukemia: lack of prognostic significance.

Abstract

Gene-promoter methylation is an epigenetic mechanism of transcription inactivation. In this study, the authors investigated the frequency and prognostic significance of p15 and p16 gene methylation in adult acute leukemia. The methylation-specific polymerase chain reaction (MS-PCR) was used to analyze p15 and p16 gene methylation in 49 cases of acute lymphoblastic leukemia (ALL) and 29 cases of acute myelogenous leukemia (AML). At presentation, 93 % of cases of AML (8 of 8 M1, 10 of 11 M2, 2 of 2 M4, 5 of 6 M5, and 2 of 2 M6; French-American-British classification system) showed p15 methylation, but none showed p16 methylation. In ALL, 57% (5 of 8 T-ALL, 16 of 30 common-ALL, 6 of 7 pre-B ALL, and 1 of 4 early B-precursor ALL) showed p15 methylation. Only 6% showed p16 methylation, all of whom had concomitant p15 methylation. One patient acquired p16 methylation during relapse. In 23 ALL karyotyped cases, p15 methylation was found in 6 of 9 cases with normal karyotype, 3 of 7 cases with the Philadelphia chromosome, 3 of 5 cases with complex, 1 with hyperdiploidy, and 1 with trisomy 21. Three more cases with unsuccessful karyotyping but bcr/abl fusion showed p15 methylation as well. Five ALL patients were tested serially for minimal residual disease (MRD) with MS-PCR that has a sensitivity of 10(-4) to 10(-5). All showed continuous positive MS-PCR that heralded hematologic relapse. The prognostic significance of p15 methylation was tested in ALL patients, showing no impact on complete remission, 5-year overall survival, or 5-year disease-free survival. Gene methylation of p15, but not p16, is frequent in adult acute leukemias. Methylation of p15 at diagnosis was of no prognostic significance in ALL but may be useful for monitoring MRD.