p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies

Mv, Mateos; López‐Pérez, Ricardo; Balanzategui, Ana; Mi, Gonzalez Guilabert; Fernández-Calvo, J.; Mj, Moro; Hernández, José; Caballero,; González, Marcos; Miguel, Jesús F. San

doi:10.1038/sj.thj.6200084

Cited by 33 publications

(20 citation statements)

References 9 publications

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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%

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%

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

González-Paz

Chng

McClure

et al. 2006

Blood

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“…cells (37,38). It has been identified that there is an association between hypermethylation of SOCS-1 and the pathogenesis of different tumors, including chronic myeloid leukemia, human melanoma and gastric cancer (39)(40)(41) (43) failed to detect a correlation between P16 methylation and prognostic factors. P16 hypermethylation has been associated with progression of the disease, as the frequency of this phenomena increases as the disease progresses through its different stages of evolution, beginning at 0% at the preclinical phase or monoclonal gammopathy of undetermined significance, at 0% for the asymptomatic phase, and to 41.8% for symptomatic MM and 80% for plasma cell leukemia (3,4,20,21).…”

Section: Discussionmentioning

confidence: 99%

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission

Martínez-Baños

Sánchez-Hernández

Jiménez

et al. 2017

Experimental and Therapeutic Medicine

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“…Recent studies revealed that the genetic predisposing factors involved in microsatellite polymorphism (7), single nucleotide polymorphism (SNP) (8,9), methylation (10), mutation as well as deletion (11). Various cytokines such as IL-6, TNF-α, IL-1β and immune regulatory molecules like CTLA-4 (cytotoxic T-lymphocyte antigen-4) as well as proto-oncogene such as p53, p16, nuclear factor IκB, etc., are reported to be the predisposing factors (11)(12)(13)(14)(15). In order to investigate the laboratory diagnostic characters of monoclonal gammopathies in large scale in China as well as to analyze the putative genetic predisposing factors, here in this study, we studied the immunological features of 2,007 cases of monoclonal gammopathies from 10,682 suspected samples for laboratory diagnostic confirmation or exclusion with serum protein electrophoresis (SPE), immunofixation electrophoresis (IFE), immunoglobulin (Ig) quantitation (rate nephelometry) as well as urine free light chain ELISA.…”

Section: Introductionmentioning

confidence: 99%

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

Wang

Gao

et al. 2008

Cell Mol Immunol

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p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies

Abstract: These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.

Cited by 33 publications

References 9 publications

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

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

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

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