CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer.

Sora Jeon,Yourha Kim,Young Jeong,Chan Jung,Ja Bae

doi:10.3390/cancers10110437

Abstract

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease.

Highlights

Thyroid cancers constitute the majority of endocrine malignancies
Cancers 2018, 10, x expression in thyroid tumors. (a) The AA genotype is associated with high levels of CCND1b mRNA
(b) This tumor shows the nuclear features of papillary thyroid carcinoma characterized by nuclear enlargement, overlapping, and membrane irregularities (×400). (c) Immunohistochemical staining positive for cyclin D1a (c, ×100) and negative for cyclin D1b (d, ×100). (e) Histologic features of an invasive encapsulated follicular variant of papillary thyroid carcinoma (×40). (f) Positive immunostaining for cyclin D1a demarcates the site of invasive growth

Summary

Introduction

Thyroid cancers constitute the majority of endocrine malignancies. Differentiated thyroid cancers, arising from follicular cells, constitute more than 95% of all thyroid cancers and are histologically classified as either papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, or poorly differentiated thyroid carcinoma [1]. Anaplastic thyroid carcinoma arises from follicular cells but is a highly aggressive disease, while differentiated thyroid cancer is generally considered an indolent disease. The most rapid rise in the incidence of thyroid cancer was observed in South Korea, where the rate increased nearly 15-fold from 1993 to 2011 [5,7]. This increase is primarily attributed to the rising incidence of PTC, and to that of low-risk PTC including subcentimeter-sized cancer or encapsulated follicular variant [4,7,8]. Differentiated thyroid cancers are generally considered indolent; there is a need to develop preoperative diagnostic markers that can be used to identify thyroid cancers requiring surgical removal from thyroid nodules

Methods

Results

Discussion

Conclusion