Hypermethylation of the CDKN2/pl6INK4A promotor in thyroid carcinogenesis

Functional inactivation of the p16(INK4A) gene has been reported to be involved in the development of a variety of human malignancies. In thyroid carcinomas, mutations of the p16(INK4A) gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16(INK4A) promotor methylation is an alternative mechanism for p 16 IKII 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 p16(INK4A) promotor status was compared with p16(INK4A) protein expression and patient-specific data. p16(INK4A) 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 p16(INK4A) 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 p16(INK4A) promotor methylation (p = 0.035). There was no association between p16(INK4A) promotor methylation and age and sex. These results suggest that hypermethylation of the p16 1A promotor region is a frequent and an early event during thyroid carcinogenesis and is associated with tumor progression and dedifferentiation.