Prevalence of aberrant methylation of p14ARF over p16INK4a in some human primary tumors

Domínguez, Gemma; Silva, Javier; García, José M.; Silva, José M.; Rodríguez, Rafael Gómez; Muñoz, Concepción; Chacón, Ignacio Fernández; Sánchez, Rosario; Carballido, Joaquı́n; Colás, A.E.; España, Pilar; Bonilla, Félix

doi:10.1016/s0027-5107(03)00133-7

Cited by 79 publications

(53 citation statements)

References 33 publications

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“…Methylation of p16 has been linked with poor clinical outcome in bladder tumors, colorectal cancer, and lung cancer. 31,32 In our study, and unlike previous reports, 33 we were unable to observe any major effect of p16 methylation on overall survival and progressionfree survival. Compared with previous studies, our survival analysis was performed on a large cohort of patients uniformly treated in a clinical trial setting with long-term follow-up such that there is minimal censoring.…”

Section: Discussioncontrasting

confidence: 96%

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: Discussioncontrasting

confidence: 96%

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

González-Paz

Chng

McClure

et al. 2006

Blood

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“…This shows that, the p14 ARF deletion also influenced the recurrence rate in combination with its promoter methylation. This observation is in contrast to previous reports linking p14 ARF methylation with poor prognosis (23). A study by Ogi et al is the only available report that observed an association between p14 ARF methylation and better survival in carcinoma cases but they were unable to arrive at a conclusion for such a result (24).…”

Section: Ink4acontrasting

confidence: 75%

Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma

Sailasree

Abhilash

Sathyan

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Oral cancer patients are found to have poor clinical outcome and high disease recurrence rate, in spite of an aggressive treatment regimen. The inactivation of INK4A/ARF loci is reported to be second to p53 inactivation in human cancers. The purpose of this study was to assess the prognostic significance of the molecular aberrations in the INK4A locus for effective identification of aggressive oral carcinoma cases needing alternate therapy. Materials and Methods: The study composed of 116 patients freshly diagnosed with oral carcinoma. The genetic and epigenetic status of the p16 INK4A and p14ARF genes was evaluated. The relation between these genic alterations and different treatment end points, such as residual disease (initial response), disease recurrence, and overall survival, along with the standard clinical markers, were analyzed. Results: 62% of the study cases had p16INK4A gene abnormalities, with deletion accounting for 33% and methylation for 29%. Alterations in p14 ARF gene either by deletion (12%) and/or methylation (18%) were

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“…It has been previously shown that CDKN2A inactivation by mutation is significantly more rare than deletion or epigenetic inactivation, which together account for inactivation of the gene in up to 75% of HNSCCs (24)(25)(26). Although p16/INK4A loss (whether genetic or functional) has been repeatedly demonstrated to correlate with indicators of worse prognosis, data on p14/Arf/INK4B loss (e.g., by methylation, when the genomic locus itself is not deleted) is conflicting, with one study suggesting worsened prognosis, while two others suggested improved prognosis, perhaps a result of increased radiation sensitivity (27)(28)(29). In the case of HPV + HNSCC, inactivation of the Rb pathway is achieved through expression of the HPV E7 protein, which binds RB1 and abrogates the requirement for p16/INK4A silencing.…”

Section: Figurementioning

confidence: 99%