Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma

Tanaka, Ryota; Wang, Daye; Morishita, Yukio; Inadome, Yukinori; Minami, Yuko; Iijima, Tatsuo; Fukai, Shimao; Goya, Tomoyuki; Noguchi, Masayuki

doi:10.1002/cncr.20827

Cited by 51 publications

(49 citation statements)

References 17 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: 56%

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: 56%

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

González-Paz

Chng

McClure

et al. 2006

Blood

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“…In our study, the loss of p16 expression was detected in 32 of 51 (62.7%) patients with gallbladder cancer. In addition, the loss of p16 expression has been correlated with tumor progression or with decreased survival among patients with carcinoma of the lung, pancreas and esophagus, and malignant melanoma [21,22,24] . The correlation between p16 expression and clinicopathological factors is controversial.…”

Section: Discussionmentioning

confidence: 99%

Two distinct pathways of p16 gene inactivation in gallbladder cancer

Hiroyuki¹

2007

WJG

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AIM:To examine the mechanism of inactivation of the p16 gene in gallbladder cancer, and to investigate p16 alterations and their correlation with clinicopathological features. METHODS:Specimens were collected surgically from 51 patients with gallbladder cancer. We evaluated the status of protein expression, loss of heterozygosity (LOH), homozygous deletion and promoter hypermethylation using immunohistochemistry, microsatellite analysis, quantitative real-time polymerase chain reaction (PCR) and methylation-specific PCR, respectively. In addition, mutations were examined by direct DNA sequencing. RESULTS:Homozygous deletions of the p16 gene exon2, LOH at 9p21-22, p16 promoter hypermethylation, and loss of p16 protein expression were detected in 26.0% (13/50), 56.9% (29/51), 72.5% (37/51) and 62.7% (32/51), respectively. No mutations were found. LOH at 9p21 correlated with the loss of p16 protein expression (P < 0.05). Homozygous deletion of the p16 gene, a combination LOH and promoter hypermethylation, and multiple LOH at 9p21 were significantly correlated with the loss of p16 protein expression (P < 0.05). LOH at 9p21 and promoter hypermethylation of the p16 gene were detected in 15.4% (2/13) and 92.3% (12/13) of the tumors with homozygous deletion of the p16 gene, respectively. P16 alterations were not associated with clinicopathological features. CONCLUSION:Our results suggest that LOH and homozygous deletion may be two distinct pathways in the inactivation of the p16 gene. Homozygous deletion, a combination of LOH and promoter hypermethylation, and multiple LOH are major mechanisms of p16 inactivation in gallbladder cancer.

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“…It has been reported that aberrant p16 promoter methylation is smoking habit associated, however TSGs methylation in non-smoker subjects has been detected [Liu et al, 2006;Nakata et al, 2006]. In addition, p16 promoter methylation has been shown to correlate with the progression of the malignancy in LC patients [Tanaka et al, 2005]. Taken together, p16 inactivation by promoter hypermethylation may be a useful precocity marker of LC development in high-risk subjects such as heavy smokers.…”

Section: Introductionmentioning

confidence: 99%

High frequency of p 16 promoter methylation in non-small cell lung carcinomas from Chile

et al. 2007

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The inactivation of tumour suppressor genes by aberrant methylation of promoter regions has been described as a frequent event in neoplasia development, including lung cancer. The p16 gene is a tumour suppressor gene involved in the regulation of cell cycle progression that has been reported to be inactivated by promoter methylation in lung carcinomas at variable frequencies around the world in a smoking habit dependent manner. The purpose of this study was to investigate the methylation status of the promoter region of the p16 gene in 74 non-small cell lung carcinomas from Chile. The frequency of p16 gene inactivation by promoter methylation was determined as 79.7% (59/74). When we considered histological type, we observed that p16 promoter methylation was significantly higher in squamous cell carcinomas (30/33, 91%) compared with adenocarcinomas (21/30, 70%) (p=0.029). In addition, no association between p16 promoter methylation and gender, age or smoking habit was found (p=0.202, 0.202 and 0.147 respectively). Our results suggest that p16 promoter hypermethylation is a very frequent event in non-small cell lung carcinomas from Chile and could be smoking habit-independent.

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Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma

Cited by 51 publications

References 17 publications

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

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

Two distinct pathways of p16 gene inactivation in gallbladder cancer

High frequency of p 16 promoter methylation in non-small cell lung carcinomas from Chile

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