Transcriptomic Differences in Medullary Thyroid Carcinoma According to Grade

Medullary thyroid carcinoma (MTC) is a rare cancer derived from neuroendocrine C-cells of the thyroid.

In contrast to other neuroendocrine tumors, a histological grading system was lacking until recently.

A novel two-tier grading system based on the presence of high proliferation or necrosis is associated with prognosis.

Transcriptomic analysis was conducted on 21 MTCs, including 9 high-grade tumors, with known mutational status, using the NanoString Tumor Signaling 360 Panel.

This analysis, covering 760 genes, revealed upregulation of the genes EGLN3 , EXO1 , UBE2T , UBE2C , FOXM1 , CENPA , DLL3 , CCNA2 , SOX2 , KIF23 , and CDCA5 in high-grade MTCs.

Major pathways differentially expressed between high-grade and low-grade MTCs were DNA damage repair, p53 signaling, cell cycle, apoptosis, and Myc signaling.

Validation through qRT-PCR in 30 MTCs demonstrated upregulation of ASCL1 , DLL3 , and SOX2 in high-grade MTCs, a gene signature akin to small-cell lung carcinoma, molecular subgroup A. Subsequently, DLL3 expression was validated by immunohistochemistry.

MTCs with DLL3 overexpression (defined as ≥ 50% of positive tumor cells) were associated with significantly lower disease-free survival ( p  = 0.041) and overall survival ( p  = 0.01).

Moreover, MTCs with desmoplasia had a significantly increased expression of DLL3.

Our data supports the idea that DLL3 should be further explored as a predictor of aggressive disease and poor outcomes in MTC.