DNA Methylation Age Drift Is Associated with Poor Outcomes and De-Differentiation in Papillary and Follicular Thyroid Carcinomas

SIMPLE SUMMARY: Normal human tissues contain an epigenetic clock resulting from the age-dependent DNA methylation signature, which is the so-called DNA methylation (DNAm) age and can be used to precisely predict chronological age of healthy individuals. Abnormal DNAm age drift has been implicated in cancer risk and pathogenesis. Here, we observed that highly drifted DNAm age (HDDA) occurred in approximately 1/3 tumors derived from patients with papillary and follicular thyroid carcinomas. HDDA is significantly associated with dedifferentiation of tumor cells and poor patient outcomes. Thus, HDDA may serve as a new prognostic factor for thyroid carcinoma. ABSTRACT: Alterations in global DNA methylation play a critical role in both aging and cancer, and DNA methylation (DNAm) age drift has been implicated in cancer risk and pathogenesis. In the present study, we analyzed the TCGA cohort of papillary and follicular thyroid carcinoma (PTC and FTC) for their DNAm age and association with clinic-pathological features. In 54 noncancerous thyroid (NT) samples, DNAm age was highly correlated with patient chronological age (R(2) = 0.928, p = 2.6 × 10(−31)), but drifted to younger than chronological age in most specimens, especially those from patients >50 years old. DNAm age in 502 tumors was also correlated with patient chronological age, but to a much lesser extent (R(2) = 0.403). Highly drifted DNAm age (HDDA) was identified in 161 tumors, among which were 101 with DNAm age acceleration while 60 with DNAm age deceleration. Tumors with HDDA were characterized by the robust aberrations in metabolic activities, extracellular microenvironment components and inflammation/immunology responses, and dedifferentiation. Importantly, HDDA in tumors independently predicted shorter disease-free survival of patients. Collectively, NT thyroids from TC patients have younger DNAm age, while HDDA frequently occurs in TCs, and contributes to the TC progression and poor patient outcomes. HDDA may serve as a new prognostic factor for TCs.