Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations

Endocr Pathol. 2021 Mar;32(1):35-43. doi: 10.1007/s12022-021-09664-3. Epub 2021 Jan 25.


Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis in familial MTC. We now have insight into the frequency and prognostic significance of specific RET mutations in sporadic MTC. For example, the most common RET mutation in sporadic MTC is the RET Met918Thr mutation, the same mutation that underlies MEN2B and a poor prognosticator. This mutation is relatively infrequent in medullary thyroid microcarcinomas but is over-represented in advanced-stage disease. RAS mutations are detected in 70% of sporadic, RET wild-type MTC. Although next-generation and whole-exome sequencing studies have shown that tumors that are wild-type for RET and RAS mutations essentially lack other recurrent mutations, additional pathways and epigenetic alterations have been implicated in MTC tumorigenesis. Increased insight into the clinical course of patients with familial MTC with specific RET mutations has guided treatment recommendations for these patients. Finally, an understanding of the genomics has informed treatment for patients with advanced MTC. In this review, we will examine the genomics and epigenomics of sporadic and familial MTC, along with the prognostic significance of molecular alterations, management of patients with germline RET mutations, and treatment strategies for MTC patients.

Keywords: Familial medullary thyroid carcinoma; Medullary thyroid cancer; Medullary thyroid carcinoma; RET; Sporadic medullary thyroid carcinoma.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinoma, Medullary / congenital*
  • Carcinoma, Medullary / genetics
  • Carcinoma, Medullary / pathology
  • Carcinoma, Neuroendocrine / genetics*
  • Carcinoma, Neuroendocrine / pathology*
  • Epigenesis, Genetic
  • Epigenomics*
  • Genomics*
  • Humans
  • Multiple Endocrine Neoplasia Type 2a / genetics*
  • Multiple Endocrine Neoplasia Type 2a / pathology
  • Proto-Oncogene Proteins c-ret / genetics*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology*


  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Familial medullary thyroid carcinoma
  • Thyroid cancer, medullary