Tumor suppressor gene p16 (CDKN2A) mutation status and promoter inactivation in head and neck cancer.

Purpose: Inactivation of p16 gene by CpG methylation is a frequent event in oral epithelial dysplasia. To investigate the predictive value of p16 methylation on malignant potential in oral epithelial dysplasia, we carried out the prospective cohort study. Experimental Design: One hundred one patients with histologically confirmed mild or moderate oral epithelial dysplasia were included in the present cohort study. p16 Methylation status of the oral epithelial dysplasia lesions from 93 cases was obtained by methylation-specific PCR. Progression of the oral epithelial dysplasia lesions was examined in 78 cases histologically during a 45.8 months follow-up period. The association between p16 methylation and progression of oral epithelial dysplasia was analyzed.Results: Of the 93 enrolled cases, 15 cases were lost during the follow-up because of changes of contact information, with a compliance of 83.9%. p16 Methylation was detectable in oral epithelial dysplasia lesions from 32 (41.0%) of 78 enrolled patients. Oral epithelial dysplasia-related squamous cell carcinomas were observed in 22 patients (28.2%) during the follow-up. Rate of progression to oral cancer in patients with the p16-methylated oral epithelial dysplasia was significantly higher than that with the p16-unmethylated oral epithelial dysplasia (43.8% versus 17.4%; adjusted odds ratio, 3.7; P = 0.013), especially for patients at the baseline age of ≥60 years (adjusted odds ratio, 12.0; P = 0.003) and patients with moderate oral epithelial dysplasia (adjusted odds ratio, 15.6; P = 0.022). The overall sensitivity and specificity of prediction of malignant transformation of oral epithelial dysplasia by p16 methylation were 63.6% and 67.9%, respectively. Conclusion: p16 Methylation was correlated with malignant transformation of oral epithelial dysplasia and is a potential biomarker for prediction of prognosis of mild or moderate oral epithelial dysplasia. (Clin Cancer Res 2009;15(16):5178-83)

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“…The p16/ARF inactivation rate was up to 70% to 85% in end-stage head and neck carcinomas (22)(23)(24)(25). Fig.…”

Section: Discussionmentioning

confidence: 99%

Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study

Cao

Zhou

Gao

et al. 2009

Clinical Cancer Research

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“…The frequency of p16 INK4a and DAP-kinase Promoter methylation in HNSCC M Hasegawa et al promoter methylation has been reported to range from 21 ± 47% (Reed et al, 1996;Sanchez-Cespedes et al, 2000;Riese et al, 1999;Esteller et al, 1999;Rosas et al, 2001), and 18 ± 33% (Sanchez-Cespedes et al, 2000;Esteller et al, 1999;Rosas et al, 2001) respectively; this is consistent with the prevalence of promoter methylation reported here. The prevalence of promoter methylation of the E-Cadherin gene was 36.3% in our study; to our knowledge this has not previously been reported for HNSCC.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work has demonstrated that the epigenetic transcriptional silencing by promoter methylation of tumor suppressor genes in HNSCC is a relatively common and important feature of this disease (Esteller et al, 2001;Reed et al, 1996;Sanchez-Cespedes et al, 2000;Riese et al, 1999). However, the mechanism responsible for methylating important somatic loci has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…The inactivation of the p16 INK4a gene is common in HNSCC and plays an important role in tumor development (Esteller et al, 2001;Reed et al, 1996;Sanchez-Cespedes et al, 2000;Riese et al, 1999;Nagai, 1999). We have previously shown that tobacco carcinogen exposure is associated with methylation of the p16 INK4a gene in lung cancer (Kim et al, 2001a).…”

Section: Introductionmentioning

confidence: 99%

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Patterns of gene promoter methylation in squamous cell cancer of the head and neck

et al. 2002

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“…p16 is a target commonly involved in esophageal carcinogenesis (51), and the abrogation of p16 occurs frequently in human oral cancers (52). The loss of expression of p16 has been observed in oral premalignant lesions (53,54), primary tumors of the oral cavity (55)(56)(57)(58), and squamous carcinomas of the upper aerodigestive tract (59).…”

Section: The Expression Of P16 Was Decreased In the Epithelia Of Mousmentioning

confidence: 99%

Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

Tang

Knudsen

Bemis

et al. 2004

Clinical Cancer Research

330

363

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Purpose: Squamous cell carcinoma of the oral cavity is one of the most common human neoplasms, and prevention of these carcinomas requires a better understanding of the carcinogenesis process and a model system in which cancer chemoprevention agents can be tested. We have developed a mouse model using the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in the drinking water to induce tumorigenesis in the mouse oral cavity.Experimental Design: 4-NQO was delivered by tongue painting or drinking water to two mouse strains, CBA and C57Bl/6. The incidences of oral cavity carcinogenesis were then compared. In addition, we examined the expression of some of the molecular markers associated with the process of human oral cavity and esophageal carcinogenesis, such as keratin (K) 1, K14, p16, and epidermal growth factor receptor, by immunohistochemistry.Results: After treatment with 4-NQO in the drinking water, massive tumors were observed on the tongues of both CBA and C57Bl/6 female mice. Pathological analyses indicated that flat squamous dysplasias, exophytic papillary squamous tumors (papillomas), and invasive squamous cell carcinomas were present. Immunohistochemistry analyses showed that 4-NQO changed the expression patterns of the intermediate filament proteins K14 and K1. K14 was expressed in the epithelial suprabasal layers, in addition to the basal layer, in tongues from carcinogen-treated animals. In contrast, control animals expressed K14 only in the basal layer. Moreover, we observed more bromodeoxyuridine staining in the tongue epithelia of 4-NQO-treated mice. Reduced expression of the cell cycle inhibitor, p16, was observed, whereas 4-NQO treatment caused an increase in epidermal growth factor receptor expression in the mouse tongues. Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQOtreated mice. However, no tumors were observed in the remainder of digestive tract (including the forestomach, intestine, and colon) or in the lungs or livers of 4-NQOtreated mice. These results indicate that this murine 4-NQOinduced oral and esophageal carcinogenesis model simulates many aspects of human oral cavity and esophageal carcinogenesis.Conclusions: The availability of this mouse model should permit analysis of oral cavity and esophageal cancer development in various mutant and transgenic mouse strains. This model will also allow testing of cancer chemopreventive drugs in various transgenic mouse strains.

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Tumor suppressor gene p16 (CDKN2A) mutation status and promoter inactivation in head and neck cancer.

Cited by 33 publications

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Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study

Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study

Patterns of gene promoter methylation in squamous cell cancer of the head and neck

Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

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