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Hypermethylation of the CDKN2/p16INK4A promotor in thyroid carcinogenesis
Carsten Boltze1, Stephan Zack, Claudia Quednow
1Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. carsten.boltze@medizin.uni-magdeburg.de
Abstract:
Functional inactivation of the p16INK4A gene has been reported to be involved in the development of a variety of human malignancies. In thyroid carcinomas, mutations of the p16INK4A gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16INK4A promotor methylation is an alternative mechanism for p16INK4A gene inactivation during thyroid carcinogenesis. A methylation-specific polymerase chain reaction protocol was applied. A total of 77 thyroid tumor specimens, including 18 follicular adenomas, 18 follicular carcinomas, 16 papillary carcinomas, 12 poorly differentiated carcinomas, and 13 undifferentiated carcinomas were analyzed longitudinally. In addition, 15 tumor-free thyroid tissues were investigated. The p16INK4A promotor status was compared with p16INK4A protein expression and patient-specific data. p16INK4A promotor hypermethylation was detected in 13% of non-tumorous tissue; in 33% of follicular adenomas; in 44% of papillary carcinomas; in 50% of follicular carcinomas; in 75% of poorly differentiated carcinomas; and in 85% of undifferentiated carcinomas. With the exception of two cases, the p16INK4A protein was lost as a result of promotor hypermethylation. Comparing the methylation status with tumor stage, no correlation was found. However, lymph node and distant metastasis status showed a statistically significant prevalence for the p16INK4A promotor methylation (p = 0.035). There was no association between p16INK4A promotor methylation and age and sex. These results suggest that hypermethylation of the p16INK4A promotor region is a frequent and an early event during thyroid carcinogenesis and is associated with tumor progression and dedifferentiation.
Insights
Promoter methylation of the p16INK4A gene frequently inactivates its function in thyroid cancer development. This epigenetic silencing is an early event linked to tumor progression and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The p16INK4A gene is crucial in preventing cancer, but its inactivation is uncommon in thyroid cancers via mutation or deletion.
- Investigating alternative inactivation mechanisms like promoter methylation is vital for understanding thyroid carcinogenesis.
Purpose of the Study:
- To determine if p16INK4A promoter methylation serves as an alternative gene inactivation mechanism in thyroid carcinogenesis.
- To correlate p16INK4A promoter methylation with thyroid tumor types, p16INK4A protein expression, and clinical data.
Main Methods:
- Analyzed p16INK4A promoter methylation status using methylation-specific polymerase chain reaction in 77 thyroid tumor specimens and 15 normal tissues.
- Compared methylation status with p16INK4A protein expression and clinicopathological data, including tumor stage, metastasis, age, and sex.
Main Results:
- p16INK4A promoter hypermethylation increased with tumor dedifferentiation, found in 13% of normal tissue up to 85% in undifferentiated carcinomas.
- Promoter hypermethylation correlated with loss of p16INK4A protein expression in most cases.
- Hypermethylation was significantly associated with lymph node and distant metastasis (p = 0.035), but not tumor stage, age, or sex.
Conclusions:
- p16INK4A promoter hypermethylation is a frequent and early event in thyroid carcinogenesis.
- This epigenetic alteration contributes to thyroid tumor progression, dedifferentiation, and metastatic potential.
- p16INK4A promoter methylation represents a key mechanism for p16INK4A gene inactivation in thyroid cancer.