The p16 (CDKN2a/INK4a) Tumor-Suppressor Gene in Head and Neck Squamous Cell Carcinoma: A Promoter Methylation and Protein Expression Study in 100 Cases

Ai, Lingbao; Stephenson, Krystal K.; Ling, Wenhua; Zuo, Chunlai; Mukunyadzi, Perkins; Suen, James Y.; Hanna, Ehab Y.; Fan, Chun Yang

doi:10.1097/01.mp.0000085760.74313.dd

Cited by 86 publications

(80 citation statements)

References 16 publications

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“…The lack of cyclin D mediated phosphorylation of the retinoblastoma (Rb) protein results in the inactivation of the cell cycle in phase G1 [17]. Several reports suggest that reduced expression or the lack of p16 ink4 protein correlates with poor prognosis of HNSCC [18,19], which we confirmed in our tested patient cohort. Recent reports have revealed that p16 ink4 -expression is associated with HPV-positivity, implying that p16 ink4 can be a surrogate marker for HPV detection.…”

Section: Discussionsupporting

confidence: 77%

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

Szentkúti

Dános

Brauswetter³

et al. 2014

Pathol. Oncol. Res.

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Head and neck squamous cell carcinomas (HNSC C) show diverse clinicopathological features and are mostly linked with poor outcome. In this study, we tested if the expression of tumor growth, cell cycle and basement membrane anchorage related biomarkers allow prognostic and clinicopathological stratification of HNSCC. Archived HNSCC samples from 226 patients included into tissue microarrays (TMA) were tested using immunohistochemistry. Histopathological evaluation and the analysis of immunostaining for EGFR, Ki67, p53, p16 ink4 and Collagen XVII proteins were carried out in digital whole slides. Statistical evaluation was carried out using Pearson's Chi-square test and Kaplan-Meier survival analysis. In the tested cohort, hypopharyngeal cancers had the least favorable, and glottic cancers had the most favorable prognosis. High Ki67 positive tumor cell fractions were associated with significantly worse prognosis and elevated rate of lymph node metastasis. Both Ki67 and EGFR expression correlated significantly with the tumor localization. Ki67 index was the highest in the hypopharyngeal region and it proved to be the lowest in the glottic region. EGFR expression was the highest in the oral cavity and the lowest in the glottic region. The survival rate of patients with p16 ink4

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Section: Discussionsupporting

confidence: 77%

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

Szentkúti

Dános

Brauswetter³

et al. 2014

Pathol. Oncol. Res.

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“…In one case, p16 protein expression is accompanied by positive p16 promoter methylation (Table 1). This has been previously documented in another study 18 and could be due to intratumor heterogeneity of methylation pattern or the presence of minor component of tumor cells that showed epigenetic silencing of the p16 gene. Nevertheless, these results indicate that approximately Figure 4 DNA sequence of methylation-specific PCR products: W, a wild-type DNA sequence; U, bisulfite-modified unmethylated DNA sequence.…”

Section: Discussionmentioning

confidence: 91%

“…Known positive and negative cases from our previous studies on head and neck carcinoma were used as control. 18 Two pathologists (QH and CYF) evaluated the immunohistochemical staining results independently.…”

Section: Immunohistochemical Staining For the P16 Proteinmentioning

confidence: 99%

Promoter hypermethylation and protein expression of the p16 gene: analysis of 43 cases of B-cell primary gastric lymphomas from China

Huang

Zhang

et al. 2004

Modern Pathology

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The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. The p16 protein is considered to be a negative regulator of the pathway. Promoter hypermethylation resulting in inactivation of the p16 gene has been found in various hematopoietic malignancies, including non-Hodgkin's lymphoma, and may play a role in transformation/clinical aggressiveness of those tumors. However, the p16 protein expression in primary gastric lymphoma has not been studied. In this study, we characterize protein expression and promoter hypermethylation of the p16 gene in B-cell primary gastric lymphomas from China. In all, 43 cases of B-cell primary gastric lymphoma were investigated. They consisted of 24 (56%) cases of diffuse large-cell lymphoma, 12 (28%) cases of extranodal marginal zone lymphoma, six (14%) cases of extranodal marginal zone lymphoma with large-cell transformation and one (2%) case of follicular lymphoma. Loss of p16 protein expression was found in 34 (79%) out of 43 cases, while the remaining nine (21%) cases showed positivities for the p16 protein. All 43 cases were further characterized by methylation-specific polymerase chain reaction (PCR) to analyze p16 promoter hypermethylation status. In total, 11 (26%) of 43 cases were positive for p16 promoter hypermethylation. Among those, 10 (30%) out of the 33 cases negative for the p16 immunostaining showed promoter hypermethylation, whereas only one (10%) out of the 10 cases that were positive for the p16 immunostaining displayed promoter hypermethylation. Of the 43 cases, 30 had limited pathologic data at the time of resection. Primary gastric lymphoma involved extragastric sites (lymph node or liver) in 17 (57%) of 30 cases, while the remaining 13 (43%) cases were only limited to the stomach. Loss of p16 protein expression was found in 14 (82%) of 17 cases with extragastric involvement and in 11 (85%) of 13 cases without such involvement. In conclusion, loss of p16 protein expression is frequent in those B-cell primary gastric lymphomas and approximately one-third of such loss correlated with promoter hypermethylation. Despite limited pathologic data, loss of p16 protein expression appears not to be correlated with extragastric involvements.

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“…The frequency of methylation was found to be approximately 30% in head and neck squamous cell carcinoma specimens obtained from surgically removed tumors (1)(2)(3)(4)(5)(6)(7)(8)(9). Although several reports have described the hypermethylation of the promoter region of the p16 tumor suppressor gene in oral cancer and in cancers of the pharynx and larynx, there have not been any reports which point out differences in the frequencies of the methylation among those cancers.…”

Section: Discussionmentioning

confidence: 94%

Differences between oral cancer and cancers of the pharynx and larynx on a molecular level

et al. 2011

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Abstract. In order to elucidate differences between oral cancers and cancers of the pharynx and larynx, we investigated the genetic and epigenetic changes in these tumors using molecular biology methods. Methylation of the promoter region of the p16 tumor suppressor gene was examined using methylation-specific polymerase chain reaction in specimens from 47 oral, 39 pharyngeal and 35 laryngeal squamous cell carcinomas. These specimens were also characterized for allelic loss of certain areas of the genome, i.e., 3p22, 9p21 and 17p13 (TP53). The frequency of methylation of the promoter region of the p16 gene in tongue cancers (35.3%) was significantly higher than in pharyngeal (12.8%) and laryngeal cancers (11.4%) (p=0.046 and p=0.039, respectively). The frequency of methylation in tumors of female patients (47.1%) was significantly higher compared to tumors of male patients (15.4%) (p=0.0067). In contrast, the frequency of the loss of heterozygosity (LOH) at 3p21 in pharyngeal cancers (66.7%) was significantly higher than in oral cancers (20.0%) (p=0.0006). The frequencies of LOH at 17p13 in pharyngeal (71.0%) and laryngeal cancers (73.1%) were also significantly higher than in oral cancers (36.1%) (p=0.009 and p=0.009, respectively). Our results indicate that there are marked differences in the frequencies of the hypermethylation of genes and allelic loss between oral cancers and cancer of the pharynx and larynx. Although all of these tumors were diagnosed as squamous cell carcinomas, the process of carcinogenesis may be different in tumors located in various parts of the head and neck. Loss of function of tumor suppressor genes by allelic loss gives rise to tumors in the pharynx and larynx, while loss of function due to methylation of the promoter regions of those genes is related to carcinogenesis in the oral cavity.

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The p16 (CDKN2a/INK4a) Tumor-Suppressor Gene in Head and Neck Squamous Cell Carcinoma: A Promoter Methylation and Protein Expression Study in 100 Cases

Cited by 86 publications

References 16 publications

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

Correlations Between Prognosis and Regional Biomarker Profiles in Head and Neck Squamous Cell Carcinomas

Promoter hypermethylation and protein expression of the p16 gene: analysis of 43 cases of B-cell primary gastric lymphomas from China

Differences between oral cancer and cancers of the pharynx and larynx on a molecular level

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