Somatic genomic profiling reveals clinically relevant heterogeneity in RAS-mutant sporadic medullary thyroid carcinoma

Objective Sporadic medullary thyroid carcinoma (sMTC) is predominantly driven by somatic RET or RAS mutations, although the molecular basis of disease heterogeneity remains incompletely understood. Our study aims to characterize molecular heterogeneity in sMTC in order to identify pathways that may improve patient’s stratification and support more personalized clinical management strategies. Methods Deep targeted next-generation sequencing of 31 neuroendocrine- and cancer-related genes was performed on tumor samples from 94 patients with sMTC to characterize the somatic mutational landscape beyond canonical drivers. Results RET and RAS mutations were detected in 53% and 29% of cases, respectively, while 18% of tumors lacked both alterations. Variant allele frequency (VAF) analysis demonstrated a significant positive correlation between driver mutation burden and tumor size in both RET - and RAS -mutant tumors, supporting the clonal contribution of these alterations. Additional oncogenic variants were identified in genes involved in DNA damage response and epigenetic regulation, including ATM and KMT2A . Notably, within the RAS -mutant subgroup, the presence of co-occurring oncogenic alterations was associated with more advanced T status (T3-T4, p = 0.0181) at diagnosis and lower biochemical cure rates ( p = 0.02) at the follow-up compared with tumors harboring isolated RAS mutations, supporting the clinical relevance of extended genomic profiling in RAS -mutant sMTC. Conclusions Overall, these findings highlight additional oncogenic alterations potentially involved in tumor progression and suggest that extended targeted profiling may provide clinically relevant information on molecular heterogeneity in sMTC, particularly within RAS -mutant tumors.