Methylation status of nine tumor suppressor genes in multiple myeloma

Abstract

Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a , 42.8%; p15 INK4b , 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RARb, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P \ 0.001) and RARb (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RARb (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P \ 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RARb hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.

Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma

“…One of the earliest reports of epigenetic aberrations in MM was of DNA hypermethylation in the promoter CpG islands of p15 and p16 [8-10]. Tumor-specific hypermethylation has also been found in the promoter regions of various tumor suppressors and other tumor-related genes, including BNIP3 , DAPK and RASD1 , which are associated with prognosis and drug resistance in MM [11-14]. Unexpectedly, however, recent advances in genome-wide analysis revealed that the number of methylated genes declines markedly with the progression of malignant transformation of plasma cells [15,16].…”

Epigenetic Modulating Agents as a New Therapeutic Approach in Multiple Myeloma

“…In line with this, multiple studies using MM cell lines and primary MM samples have revealed loci-specific hypermethylation which is summarized in Table 1 and has been reviewed elsewhere [49]. Moreover, methylation of several of these genes was associated with poor prognosis of MM patients and include SPARC , BNIP3 [50], DAPK , RARβ [51], EGLN3 [52], DLC-1 [53], CDH-1 [54], DCC , TGFβR2 [55], CD9 [56] and p16 [57]. One study even proposed that TP73 , p15 , p16 and ARF methylation is an early event in MM pathogenesis because of hypermethylation in both MGUS and MM samples, while SOCS-1 methylation was present in higher abundance in MM samples compared to MGUS and thus may be involved in the progression of MGUS to MM [58].…”

DNA Methylation of Tumor Suppressor Protein-Coding and Non-Coding Genes in Multiple Myeloma

“…In contrast, it is counteracted by cyclin-dependent kinase inhibitors, including the INK4 family and the CIP/KIP family, resulting in cell cycle arrest [54,55]. Indeed, frequent methylation-mediated loss of CDKN2A and CDKN2B, members of the INK4 family, has been demonstrated in myeloma patients at diagnosis [49][50][56][57][58][59][60][61][62][63]. Furthermore, methylation of CDKN2A was shown to be associated with disease progression and inferior survival for myeloma patients [49,57,59,61].…”

“…Meanwhile, the JAK/STAT signaling pathway is controlled by three major classes of negative regulators, including SOCS, PIAS, and PTP (also known as SHP). Among them, methylation of SHP1 was frequently detected in myeloma plasma cells at diagnosis [56][57][75][76]. Importantly, Chim et al showed that restoration of SHP1 was associated with reduced level of phosphorylated STAT3 and therefore inactivation of the JAK/STAT signaling pathway, thereby illustrating the tumor suppressor role of SHP1 in myeloma [75].…”