LAUSR

Simple Summary Medullary thyroid carcinoma (MTC) is a rare but clinically relevant tumor based on its aggressiveness and the limited therapeutic opportunities currently available for advanced cases. A better understanding of the mechanisms of MTC development is crucial to identify more effective means of intervention and therapies. Several studies have shown that RET and RAS genes play a central role in MTC. However, little is known about the signaling processes operating downstream of these genes. Here, we report mutation and gene expression profiles in proprietary sporadic MTCs, including both primary and metastatic tumors. We show that tumors derived from the same patient display similar expression profiles and that the latter can be used to obtain information about specific downstream signaling, identifying distinct molecular subtypes. Furthermore, by reviewing the relevant literature, we highlight that, along with RET and RAS, other less frequent genes are emerging as possible new players in MTC. Abstract Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although RET and RAS genes are recognized drivers in MTC, associated downstream signaling pathways are largely unknown. In this study, we report 17 sporadic MTCs, collected at our institution, comprising patient-matched primary and lymph node metastatic tumors investigated for mutational and transcriptional profiles. As we identified two uncommon RET deletions (D898_E901del and E632_L633del), we also performed a literature review and meta-analysis to assess the occurrence of unconventional alterations in MTC, focusing on next-generation sequencing studies. We found that new gene alterations are emerging, along with the known RET/RAS drivers, involving not only RET by multiple concurrent mutations or deletions but also other previously underestimated cancer-related genes, especially in sporadic MTCs. In our MTC gene profiles, we found transcriptome similarity between patient-matched tissues and expression of immune genes only by a few samples. Furthermore, we defined a gene signature able to stratify samples into two distinct signaling types, termed MEN2B-like and MEN2A-like. We provide an updated overview of the MTC mutational spectrum and describe how transcriptional profiles can be used to define distinct MTC signaling subtypes that appear to be shared by various gene drivers, including the unconventional ones.