Researchers identified a gene signature that could classify mutations seen in medullary thyroid carcinoma (MTC) according to the signaling pathways and published their findings in Cancers.

The meta-analysis conducted by Minna et al included 17 patients with MTC from their medical center and 37 patients described among 16 different publications to assess the frequency of traditional and new mutations in their biochemical pathways. As expected, mutations in RET were the most common, specifically RET M918T, followed by RET C634.

RAS point mutations were also relatively frequent, mostly H/KRAS in codons Q61 and G12/13. Although still considered rare, 5.3% of the sporadic cases showcased RET del/delins mutations with a tendency to increase over time. The proposed gene signature allows identifying which is the signaling type involved in each case of MTC.

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The authors identified 2 pathways with overlapping and distinct clinical features, the multiple endocrine neoplasia type 2 A (MEN2A)-like, and the multiple endocrine neoplasia type 2 B (MEN2B)-like. This classification detects germline gain-of-function mutations in the tyrosine kinase receptor RET which in turn creates different genotype-phenotype relationships. In the case of MEN2A, most mutations are in cysteine residues of RET, whereas MEN2B regards mutations in the RET intracellular tyrosine kinase domain.

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“Three patients harboring the two most frequent RET deletions found in MTC (i.e., exon11 E632-L633del and exon15 D898-E901del) were investigated herein,” the authors said. “This indicates that different RET deletions activate distinct signaling cascades consistent with their localization in RET-specific functional domains (i.e., the extracellular cysteine-rich domain for exon11 lesions and the intracellular tyrosine kinase domain for exon 15–16 lesions, respectively).”

These findings yield a better understanding of this rather rare but greatly aggressive tumor. MTC accounts for less than 3% of neoplastic thyroid diseases but has high mortality rates and very scarce effective treatment options.

“These signaling types are identified both in the presence of canonical drivers, such as RET M918T and RAS mutations, and in the presence of rare alterations, such as RET deletions. Particularly for MTCs with uncommon alterations, this represents a useful finding to better understand the downstream signaling mediated by these less frequent and still poorly investigated lesions,” the authors concluded.


Minna E, Romeo P, Dugo M, et al. Medullary thyroid carcinoma mutational spectrum update and signaling-type inference by transcriptional profiles: literature meta-analysis and study of tumor samples. Cancers (Basel). Published online April 13, 2022. doi:10.3390/cancers14081951