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. 2024 Sep;35(3):207-218.
doi: 10.1007/s12022-024-09817-0. Epub 2024 Jul 3.

Transcriptomic Differences in Medullary Thyroid Carcinoma According to Grade

Ignacio Ruz-Caracuel  1   2 , Tamara Caniego-Casas  3   4 , Teresa Alonso-Gordoa  5 , Irene Carretero-Barrio  3   4   6 , Carmen Ariño-Palao  3   6 , Almudena Santón  3   4 , Marta Rosas  3 , Héctor Pian  3 , Javier Molina-Cerrillo  5 , Patricia Luengo  7 , José Palacios  3   4   6
Affiliations

Transcriptomic Differences in Medullary Thyroid Carcinoma According to Grade

Ignacio Ruz-Caracuel et al. Endocr Pathol. 2024 Sep.

Abstract

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.

Keywords: DLL3; Endocrine pathology; Medullary thyroid carcinoma; Neuroendocrine neoplasia; Thyroid; Transcriptomic.

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Conflict of interest statement

Ignacio Ruz-Caracuel has received lecture fees and travel reimbursement from Lilly. Teresa Alonso-Gordoa has received research funding, honoraria, and nonfinancial support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche, MSD. Javier Molina-Cerrillo has received research funding, honoraria, and nonfinancial support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Janssen, BMS, Astellas, Roche, and MSD.

Figures

Fig. 1
Fig. 1
Expression profile according to MTC grade. A Unsupervised clustering analysis based on molecular pathways did not cluster separately high-grade from low-grade MTC. B Volcano plot showing differentially expressed genes according to grade. C Venn diagram including the genes differently expressed among three morphological conditions: high-grade vs low-grade MTC, proliferation index ≥ 5% vs < 5%, and tumors with necrosis present vs absent. D Top fifteen overrepresented pathways considering the genes differentially expressed between high-grade and low-grade MTC
Fig. 2
Fig. 2
Panel of genes validated by qRT-PCR. *p < 0.001
Fig. 3
Fig. 3
DLL3 immunohistochemical expression in MTC. A Low-grade MTC and B high-grade MTC with low expression of DLL3 (DLL3, 40 ×). C Low-grade MTC with a high cytoplasmic expression of DLL3 of variable intensity among tumor cells (DLL3, 40 ×). D High-grade MTC with high expression of DLL3 and central comedonecrosis (DLL3, 20 ×). E High-grade MTC with prominent desmoplasia (H-E, 10 ×) and F a high expression of DLL3 (DLL3, 10 ×). G Strong perinuclear dot-like staining in scattered cells (DLL3, 40 ×). H Non-specific granular staining in normal follicles (DLL3, 40 ×)
Fig. 4
Fig. 4
Kaplan–Meier survival curves according to grade and DLL3 expression. A Disease-free survival according to grade. B Overall survival according to grade. C Disease-free survival according to DLL3 positive expression. D Overall survival according to DLL3 positive expression
See this image and copyright information in PMC

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