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

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.