J Korean Assoc Oral Maxillofac Surg.  2012 Apr;38(2):101-109. 10.5125/jkaoms.2012.38.2.101.

Impact of methylation of the p16INK4a gene on the prognosis ofhead and neck squamous cell carcinoma patients

• Lee EH
• Hwang DS
• Shin SH
• Kim UK
• Chung IK
• Kim YD

• KMID: 2189706
• DOI: http://doi.org/10.5125/jkaoms.2012.38.2.101

Abstract

OBJECTIVES
The inactivation of the tumor suppressor gene p16INK4a plays an important role in the development of malignant tumors, including oral squamous cell carcinoma. The p16 gene is involved in the p16/cyclin-dependent kinase/retinoblastoma (Rb) gene pathway of cell cycle control. The p16 protein is considered a negative regulator of this pathway. The p16 gene encodes an inhibitor of cyclin-dependent kinases 4 and 6 which regulate the phosphorylation of the retinoblastoma gene and G1 to S phase transition in the cell cycle. However, the p16 gene can lose its functionality through point mutations, loss of heterozygosity or methylation of its promoter region.
MATERIALS AND METHODS
In this study, the authors analyzed the correlation between various clinicopathological findings-patient age, gender and smoking, disease recurrence, tumor size, stage, and differentiation- and p16 protein expression or p16 promoter hypermethylation in 59 cases of head and neck squamous cell carcinoma.
RESULTS
The results revealed p16 protein expression and p16 promoter hypermethylation in 28 cases (47.5%) and 21 cases (35.6%), respectively, of head and neck squamous cell carcinoma. However, neither p16 protein expression nor p16 promoter hypermethylation had any statistical influence on clinicopathological findings or survival rate.
CONCLUSION
This data, and a review of the literature, suggest that p16 promoter hypermethylation cannot yet be used as an independent prognostic factor influencing carcinogenesis, but must be considered as an important factor along with other genetic alterations affecting the pRb pathway.

Keyword

Methylation; Epigenomics; Prognosis; Neoplasms

MeSH Terms

Carcinoma, Squamous Cell
Cell Cycle
Cell Cycle Checkpoints
Cyclin-Dependent Kinases
Epigenomics
Genes, p16
Genes, Retinoblastoma
Genes, Tumor Suppressor
Head
Humans
Loss of Heterozygosity
Methylation
Neck
Phosphorylation
Point Mutation
Prognosis
Recurrence
S Phase
Smoke
Smoking
Cyclin-Dependent Kinases
Smoke

Figure

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  Fig. 1 Immunohistochemical staining for p16. In (A), immunohistochemistry shows nuclear/cytoplasmic staining in majority of tumor cells (H&E staining, ×200). In (B), p16 protein expression was not observed in the tumor cells (H&E staining, ×200).

• 

  Fig. 2 Methylation-specific PCR analysis of p16INK4a PCR products amplified using unmethylated (U) and methylated (M) specific primers. (PCR: polymerase chain reaction, S: sample, C: control)

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  Fig. 3 Effect on survival of p16 protein expression. Non-expressed p16 protein was not associated with a significant reduction in overall survival (P=0.1031).

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  Fig. 4 Effect of p16INK4a promoter hypermethylation. Methylated p16INK4a was not associated with a significant reduction in overall survival (P=0.6392).

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