Methylation Markers for Early Detection and Differentiation of Follicular Thyroid Cancer Subtypes.

Josena K Stephen,Jason Merritt,Maria J Worsham,Kang Mei Chen,Dhananjay Chitale,George Divine

doi:10.5539/cco.v4n2p1

Abstract

Thyroid cancer has the fastest rising incidence rates and is the fifth most common cancer in women. There are four main types of which the papillary and follicular types together account for >90%, followed by medullary cancers (3%−5%) and anaplastic carcinomas (<3%). For individuals who present with early stage disease of papillary and follicular cancers, there are no accurate markers to predict whether they will develop metastatic or recurrent disease. Our immediate goal is to molecularly differentiate follicular cancer subtypes for enhanced classification. Promoter methylation status of genes with reported associations in thyroid cancer (CASP8, CDKN2A, DAPK1, ESR1, NIS, RASSF1 and TIMP3) were examined in a cohort of follicular thyroid cancers comprising of 26 Hurthle and 27 Classic subtypes utilizing quantitative methylation-specific PCR. RASSF1 was differentially methylated in Classic tumor tissue compared to Hurthle (p<0.001). Methylation of RASSF1 pointed to racial group differences between African Americans and Caucasian Americans (p=0.05). Extra thyroidal extension was found to be associated with DAPK1 (p=0.014) and ESR1 (p=0.036) methylation. Late stage disease was associated with older age (p<0.001) and methylation of DAPK1 (p=0.034) and ESR1 (p=0.035). The methylation status of RASSF1, DAPK1 and ESR1 suggests the utility of methylation markers to molecularly differentiate thyroid cancer subtypes for enhanced classification and early detection of thyroid cancer.

Highlights

Thyroid cancer (TC) is the most common endocrine malignancy, accounting for 95% of all endocrine malignancies (Boufraqech, Patel, Xiong, & Kebebew, 2013), and which has an increasing incidence for 1999-2008: going up by an estimated 6.2% per year for men and 7.3% per year for women (Simard, Ward, Siegel, & Jemal, 2012)
Promoter methylation status of genes with reported associations in thyroid cancer (CASP8, CDKN2A, DAPK1, ESR1, NIS, RASSF1 and TIMP3) were examined in a cohort of follicular thyroid cancers comprising of Hurthle and Classic subtypes utilizing quantitative methylation-specific PCR
CASP8 and CDKN2A were not methylated in any samples

Summary

Introduction

Thyroid cancer (TC) is the most common endocrine malignancy, accounting for 95% of all endocrine malignancies (Boufraqech, Patel, Xiong, & Kebebew, 2013), and which has an increasing incidence for 1999-2008: going up by an estimated 6.2% per year for men and 7.3% per year for women (Simard, Ward, Siegel, & Jemal, 2012). Neoplasias of the thyroid have been largely ignored because of the overall favorable prognosis of papillary thyroid cancers (PTC) and follicular thyroid cancers (FTC), with 5-year survival rates of approximately 98% when submitted to timely and appropriate treatment Despite this favorable prognosis, the increasing incidence is of concern. No significant progress has been made to improve survival. Those diagnosed at late stages have a devastating 5-year survival rate of under 60% (Weber & Eng, 2005). Despite advances on scientific and clinical fronts, many advanced thyroid cancers remain incurable

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