Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

Bin Xu, Kartik Viswanathan, Mahsa S. Ahadi, Sara Ahmadi, Bayan Alzumaili, Mohamed Amine Bani, Eric Baudin, David Blake Behrman, Marzia Capelletti, Nicole G. Chau, Federico Chiarucci, Angela Chou, Roderick Clifton-Bligh, Sara Coluccelli, Dario de Biase, Antonio De Leo, Snjezana Dogan, James A. Fagin, Talia L. Fuchs, Anthony Robert GloverJulien Hadoux, Ludovic Lacroix, Livia Lamartina, Daniel J. Lubin, Catherine Luxford, Kelly Magliocca, Thais Maloberti, Abhinita S. Mohanty, Fedaa Najdawi, Aradhya Nigam, Alexander James Papachristos, Andrea Repaci, Bruce Robinson, Jean Yves Scoazec, Qiuying Shi, Stan Sidhu, Erica Solaroli, Mark Sywak, R. Michael Tuttle, Brian Untch, Justine A. Barletta, Abir Al Ghuzlan, Anthony J. Gill, Ronald Ghossein, Giovanni Tallini, Ian Ganly

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent mo- lecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

Original languageEnglish
Pages (from-to)167-176
Number of pages10
Issue number2
StatePublished - 1 Feb 2024
Externally publishedYes


  • RAS
  • RET
  • grade
  • medullary thyroid carcinoma
  • prognosis


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