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Somatic genomic profiling reveals clinically relevant heterogeneity in RAS-mutant sporadic medullary thyroid

Edoardo Ruggeri1,2, Simona Censi1,2, Loris Bertazza1,2

  • 1Department of Medicine (DIMED), University of Padua, Padua, Italy.

Journal of Clinical & Translational Endocrinology
|May 13, 2026
PubMed
Abstract

Insights

This study reveals that sporadic medullary thyroid carcinoma (sMTC) has more genetic drivers than previously known. Extended genomic profiling in RET- and RAS-mutant sMTC can improve patient stratification and personalized treatment strategies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Sporadic medullary thyroid carcinoma (sMTC) is primarily driven by RET or RAS mutations.
  • The full spectrum of molecular drivers and their role in sMTC heterogeneity is not well understood.

Purpose of the Study:

  • To characterize the molecular heterogeneity of sporadic medullary thyroid carcinoma (sMTC).
  • To identify molecular pathways for improved patient stratification and personalized clinical management.

Main Methods:

  • Deep targeted next-generation sequencing of 31 cancer-related genes was performed on 94 sMTC tumor samples.
  • Analysis included somatic mutational landscape, variant allele frequency, and correlation with clinical parameters.

Main Results:

  • RET and RAS mutations were found in 53% and 29% of tumors, respectively; 18% lacked both.
  • Driver mutation burden correlated positively with tumor size.
  • Additional oncogenic variants in DNA damage response (e.g., ATM) and epigenetic regulation (e.g., KMT2A) genes were identified.
  • In RAS-mutant sMTC, co-occurring alterations were linked to advanced T status and lower cure rates.

Conclusions:

  • Extended targeted profiling reveals clinically relevant molecular heterogeneity in sMTC.
  • Findings particularly highlight the importance of comprehensive genomic analysis in RAS-mutant sMTC for personalized treatment.
Keywords:
Biochemical cureNGS somatic panelPrecision medicine strategiesRAS-mutant tumorsT status

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