Genome-wide DNA methylation profiling identifies clinically relevant subgroups in medullary thyroid cancer

Abstract Background Medullary thyroid cancer (MTC) is rare and well treatable by surgery in early stages. However, early lymph node involvement is common and significantly worsens prognosis. Advanced MTC is treated with tyrosine kinase inhibitors, offering promising yet variable response rates. Current predictors of tumour aggressiveness are limited and tissue characteristics, driving recurrence or persistent disease remain poorly understood. This study aims to investigate genome-wide DNA methylation profiles of patients with MTC, potentially allowing to identify biologically and clinically meaningful subgroups with prognostic impact and predictive factors to systemic treatment. Methods Forty FFPE MTC tissue blocs were analysed for DNA-methylation profiles, using the Infinium Methylation EPIC BeadChip Kit (Illumina). Each array accommodates eight samples and features more than 850,000 methylation sites across the genome. Patient samples were stratified into subgroups based on clinical parameters and established markers of tumour aggressiveness. Methylation patterns were subsequently compared between these subgroups to identify characteristic epigenetic differences. Results Analyses of the methylation patterns demonstrated significant epigenetic variation between several meaningful subgroups. WHO low-grade and high grade MTC exhibited markedly different methylation patterns, reflecting distinct biological behaviour. Patients with germline RET mutations and somatic RET mutations could also be separated clearly. Additionally, subgroups based on preoperative calcitonin levels demonstrated characteristic differences in methylation patterns. Conclusion Our findings highlight a strong potential of epigenetic profiling to show biological heterogeneity of MTC and therefore discriminate subgroups with prognostic and predictive impact. This may serve as a basis for improved prognostic assessment and personalised therapeutic strategies in the future.