FREQUENT HYPERMETHYLATION OF P16 AND P15 GENES IN MULTIPLE-MYELOMA

Both p16 and p15, encoded by the genes located on chromosome 9p21, are inhibitors of cyclin-dependent kinases (CDK4/6) and the upstream regu lators of Rb function. In hematopoietic malignancies, deletion of p16/ p15 locus has been shown to be highly specific to lymphoid, and more p articularly from B-lineage malignancies except multiple myeloma (MM). To investigate whether these genes are inactivated by deletions, mutat ions, and hypermethylation of the 5' CpG islands, we examined 12 MM pa tients by Southern hybridization and polymerase chain reaction-single- strand conformation polymorphism (PCR-SSCP) analysis. No deletions nor mutations of the p16 and p15 genes were found. However, hypermethylat ion was observed in 75% for p16 and 67% for p15 in our group of MM pat ients. Such high frequencies of involvement of these genes in MM make them hitherto the most common genetic abnormalities in this disease. C oncomitant hypermethylation, uncommon thus far in the literature of th e study of these genes, is a rather common phenomenon, occurring in 67 % of our patient group. Moreover, hypermethylation of p16/p15 was asso ciated with blastic disease and concomitant hypermethylation of both g enes may be pathogenetically related to plasmacytoma development. Thes e results indicate that these genes are important in MM pathogenesis. Here we report, for the first time in the literature, the high inciden ces of p16 and p15 alterations in MM, not by homozygous deletions or m utations, but solely by hypermethylation of the 5' CpG islands, which may be a specific mechanism in this disease. (C) 1997 by The American Society of Hematology.