Medullary thyroid carcinoma (MTC) patients with mutations in the RET proto-oncogene have higher levels of RET mRNA expression than patients with mutations to the RAS gene or those without mutations in either gene, according to a new article published in Biomolecules.

The study found that patients with RET somatic mutations (RET+; n=39) had significantly higher expression (P =.005) of RET mRNA than patients without mutations in the RET or RAS genes (RET- and RAS-). RET+ cases also had higher expressions when compared to the group of patients with RAS+ and RET- mutations (P =.003).

In addition, the researchers discovered that all of the MTC patients (n=83) expressed the RET51 isoform, while only 86.7% of the patients expressed the RET9 isoform. The RET51 expression levels were also found to be significantly higher than RET9 levels (P <.0001).

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RET+ patients had statistically higher RET51 expression than RAS+ patients (P =.0006) as well as RET- and RAS- patients (P =.001). RET9 levels were not different between mutation groups.

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Previous research has indicated that RET51 enhances cell proliferation and motility and has a greater transforming potential than RET9. Other research has shown that RET51 expression is higher in aggressive forms of pancreatic cancer and is higher in MTC than in papillary thyroid carcinoma.

Overall, the study recruited 83 Italian MTC patients that included 39 with RET somatic mutations, 20 with RAS somatic mutations, and 24 cases with neither mutations in RET or RAS. Samples were taken from each patient during surgery and were analyzed using next-generation sequencing.

“Taking into consideration that the RET51 isoform seems to be able to confer a selective growth advantage, our previous results, showing that RET mutated cases have a high percentage of the mutated allele and that the corresponding tumors are usually bigger than not-mutated cases, are further supported,” the authors concluded.


Mulè C, Ciampi R, Ramone T, et al. Higher RET gene expression levels do not represent an Alternative RET activation mechanism in medullary thyroid carcinoma. Biomolecules. 2021;11(10):1542. doi:10.3390/biom11101542