Abstract
Background and Aims: CDKN1B (p27) is frequently downregulated in thyroid tumors, among many other cancers. To date, studies have been focused on postranscriptional downregulation of p27 (mainly on protein degradation and cytosolic mislocalization), and highlighted the key role of this gene in the tumoral process. Because of this, p27 was selected as a candidate gene to perform a case-control study to define if it is acting as a genetic risk factor to develop sporadic thyroid cancer.
Methods: We performed the first association study of CDKN1B in thyroid cancer, comparing a total of 649 sporadic Spanish cancer cases against over 400 healthy representative controls. All the main thyroid cancer subtypes were represented in our series: 274 Medullary Thyroid Carcinoma (MTC), 47 Follicular Thyroid Carcinoma (FTC) and 328 Papillary Thyroid Carcinoma (PTC), that included its principal subtypes, ‘classic PTC (cPTC) and ‘PTC follicular variant (FVPTC). Due to the lack of linkage disequilibrium along this region, we selected three putative functional polymorphisms [rs2066827 (T326G, V109G), rs34330 (-79 C>T) and rs36228499 (-838 C>A)], and genotyped them in cases and controls, either by a TaqMan assay or a Restriction Fragment Length Polymorphism (RFLP) approach. We also performed luciferase assays to evaluate the transcriptional effect of the significant SNP identified in this study.
Results and Conclusions: We found a significant association for rs34330 in FVPTC cases (OR=2.10, p-value=0.035). We also demonstrated that the risk genotype (TT) of this SNP leads to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27 promoter. We conclude that the SNP rs34330, located in p27 promoter, could be a genetic risk factor related to susceptibility to develop, at least, FVPTC. This could be explained by its effect on the p27 transcription.