title: An immunohistochemical study of p16(INK4a) expression in multistep thyroid tumourigenesis.
abstract: Normal human thyroid follicular epithelial cells exhibit a very low proliferative rate which in vitro is dramatically increased by RAS oncogene activation, resulting in clones displaying a phenotype consistent with that of a ras-induced follicular adenoma in vivo. Eventual spontaneous cessation of growth of these clones is closely correlated with increasing expression of the tumour suppressor gene p16(INK4a), suggesting that p16 may limit clonal expansion in this tumour model. We therefore hypothesised that p16 expression would also increase in vivo in follicular adenomas, and further that escape from growth control in follicular cancers would be accompanied by loss of p16 expression. This was tested using tissue microarrays, representing multiple stages of thyroid tumourigenesis. Whereas the majority of normal thyroids showed no immunostaining, p16 protein was readily detectable in follicular adenomas. Unexpectedly, however, p16 expression was also observed in follicular and papillary carcinomas. Poorly differentiated (insular) carcinomas showed either very intense staining, or a complete loss of staining. We conclude that loss of p16 is not necessary for malignant transformation in thyroid follicular cells, but that it may form one of two or more events needed for progression to more aggressive forms of thyroid cancer.
authors.affiliation: Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ball
authors.forename: Jane
authors.initials: J
authors.lastname: Bond
authors.forename: Brigitte
authors.initials: B
authors.lastname: Franc
authors.forename: Catherine
authors.initials: C
authors.lastname: Demicco
authors.forename: David
authors.initials: D
authors.lastname: Wynford-Thomas
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D019925:Cyclin A; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2