Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia

Uchida, Toshiki; Kinoshita, Tomohiro; Ohno, Toshihito; Ohashi, Haruhiko; Nagai, Hirokazu; Saito, Hidehiko

doi:10.1038/sj.leu.2401991

Cited by 45 publications

(33 citation statements)

References 35 publications

(26 reference statements)

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“…Our reported prevalence of p16 methylation falls within the range of 10% to 51% reported in previous literature. 9,[17][18][19][20][21][22][23][24][25][26] The heterogeneity in methodology and sample sizes may explain such variation among studies. Although p16 methylation is slightly (but significantly) more prevalent in MM than SMM/MGUS and may be a marker of advance disease, our data did not confirm previous studies that suggested p16 methylation may contribute in the transformation from MGUS to MM as a substantial proportion of MGUS already harbors p16 methylation.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in MM have found no mutations or deletions, but promoter methylation has been reported with an incidence of up to 58%. 9 Fewer data are available regarding inactivating abnormalities of the p16 gene in normal plasma cells, MGUS, and SMM. In this study we analyzed bone marrow samples from healthy persons and persons with MGUS, SMM, and MM for p16 promoter methylation by methylation-specific polymerase chain reaction (MS-PCR) and interstitial deletions by interphase fluorescence in situ hybridization (FISH).…”

Section: Introductionmentioning

confidence: 99%

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Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications

González-Paz

Chng

McClure

et al. 2006

Blood

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The biological and clinical implications of p16 gene methylation in multiple myeloma (MM) are still unclear despite previous studies. In this comprehensive study, using methylation-specific PCR (MS-PCR), we show that p16 methylation is relatively common and occurs in monoclonal gammopathy of undetermined significance (MGUS; n ‫؍‬ 17), smoldering multiple myeloma (SMM; n ‫؍‬ 40), and MM (n ‫؍‬ 522) at a prevalence of 24%, 28%, and 34%, respectively. However, p16 methylation does not appear to affect gene expression level. In a large cohort of patients with long-term follow-up information (n ‫؍‬ 439), there was no difference in overall survival between patients with or without p16 methylation. We also found no association between p16 methylation and the main cytogenetic categories, although it was more common among patients with 17p13.1 deletions (p53 locus), a genetic progression event in MM. In addition, p16 methylation has no apparent effect on the cycle because there was also no difference in the plasma cell labeling index (a direct measurement of proliferation) between patients with and without p16 methylation. Our results question a major role for p16 methylation in the oncogenesis of the PC neoplasm, and we now believe p16 methylation may be a marker for overall epigenetic changes associated with disease progression, with no obvious direct biological or clinical consequences. IntroductionThe retinoblastoma (Rb) checkpoint controls G 1 /S transition. 1 Abnormalities in this pathway caused either by loss of Rb or p16 function, or increased activity of cyclin D1 or CDK4/6 in the cell-cycle machinery, results in uncontrolled cell proliferation, invasion, and metastasis. [2][3][4] The p16 gene is one of the most commonly affected members of this pathway. The cyclindependent kinase 4 inhibitor p16 gene, located at 9p21, has been shown to be inactivated in a variety of tumors by deletions, point mutations, or hypermethylation of its promoter. [5][6][7] Furthermore, inactivation of this tumor suppressor gene can be important for initiation and maintenance of the transformed phenotype. 7 Reports also suggest that loss of p16 gene function is increasingly common with advancing stages of various neoplasms, suggesting that p16 inactivation may contribute to disease progression. 8 This body of evidence suggests a key role of this gene in initiation and progression during carcinogenesis.The plasma cell (PC) neoplasms range from indolent disorders (ie, monoclonal gammopathy of undetermined significance [MGUS] and smoldering multiple myeloma [SMM]) to aggressive variants (eg, active multiple myeloma [MM] and PC leukemia); indolent forms often progress to the more advanced stages. Although the genetic/cytogenetic abnormalities responsible for the PC neoplasm are becoming better understood, the role of p16 methylation, if any, is largely unknown. Studies in MM have found no mutations or deletions, but promoter methylation has been reported with an incidence of up to 58%. 9 Fewer data are available regarding inactivating ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications

González-Paz

Chng

McClure

et al. 2006

Blood

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“…However, cell lines with p15INK4b DNA methylation have lower levels of p15INK4b expression (30 cDNA copies/100 ng total RNA) compared with unmethylated cell lines (428 cDNA copies/100 ng total RNA; P Ͻ .01; unpaired t test; Figure 1B). With the exception of U-937 and AML-193 cells, expression of p16INK4a is also low in AML cell lines, even though they are free of p16INK4a DNA methylation 23,25 ( Figure 1B-C).…”

Section: H3k27me3 Is Enriched At the Ink4b-arf-ink4a Locus In Aml Celmentioning

confidence: 99%

Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Paul

Bies

Small

et al. 2010

Blood

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“…Seven (23%) of 30 MM tumors had methylated p16, whereas 12 (75%) of 16 MM cell lines had methylated p16, consistent with results published by Gonzalez-Paz et al 1 and others. [5][6][7] We determined the expression of p16 RNA in 79 tumors (including 7 with methylated p16 and 23 with unmethylated p16) and in 16 cell lines. Three cell lines (EJM, OPM-2, PE-1) with unmethylated p16 express substantial levels of p16, with the highest level of expression in EJM being comparable with small-cell lung cancer lines that express high levels of p16 (data not shown).…”

Section: Methylation and Expression Of The P16ink4a Tumor Suppressor mentioning

confidence: 99%

Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma

Dib¹,

Barlogie²,

Shaughnessy³

et al. 2007

Blood

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from this large prospective study because of the infrequency of factor V Leiden in African Americans.We were unable to repeat other measures in our original report 1 (activated protein C resistance, factor V concentration, and HRZ haplotype) to confirm no influence of the control selection error. Nevertheless, these factor V Leiden results offer confidence of the accuracy of our original report. 1 Aaron R. Folsom, for the LITE Investigators

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Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia

Cited by 45 publications

References 35 publications

Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications

Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications

Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML

Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma

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