AUTHOR=Saeed-Vafa Daryoush , Chatzopoulos Kyriakos , Hernandez-Prera Juan , Cano Pedro , Saller James J. , Hallanger Johnson Julie E. , McIver Bryan , Boyle Theresa A. 

TITLE=RET splice site variants in medullary thyroid carcinoma

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1377158

DOI=10.3389/fgene.2024.1377158

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in <italic>RET</italic>. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. <italic>RET</italic> SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC.</p><p><bold>Methods:</bold> The prevalence of <italic>RET</italic> SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare <italic>RET</italic> SSV frequency in cancers with/without a diagnosis of MTC.</p><p><bold>Results:</bold> All 25 MTCs had at least one of the two most common <italic>RET</italic> SSVs versus 0.3% of 3,599 cancers with other diagnoses (<italic>p</italic> &lt; 0.00001). The 11 cancers with non-MTC diagnoses that had the common <italic>RET</italic> SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common <italic>RET</italic> SSVs, including 4 with no identified mutational driver.</p><p><bold>Discussion:</bold> The identification of <italic>RET</italic> SSVs in all MTCs, but rarely in other cancer types, demonstrates that these <italic>RET</italic> SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these <italic>RET</italic> SSVs play a pathogenic role in MTC.</p>