Hypermethylation of the CDKN2/p16INK4A promotor in thyroid carcinogenesis.
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.
Boltze
Carsten
C
Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. carsten.boltze@medizin.uni-magdeburg.de
Zack
Stephan
S
Quednow
Claudia
C
Bettge
Silke
S
Roessner
Albert
A
Schneider-Stock
Regine
R
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D020868:Gene Silencing; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm