Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form

Mutat Res. 2013 Jan-Mar;752(1):36-44. doi: 10.1016/j.mrrev.2012.09.002. Epub 2012 Oct 8.


Medullary thyroid carcinoma (MTC) is an uncommon malignant tumor arising from the calcitonin-producing parafollicular cells (C cells) of thyroid. It accounts for 5-10% of all thyroid cancers, and it mostly occurs as a sporadic entity (sMTC), but a familial pattern (fMTC) is also possible. RET proto-oncogene germline mutations are crucial for the onset and the progression of fMTC, and the occurrence of single nucleotide polymorphisms could predispose to the sporadic form. In order to clarify the role of this gene in MTC, we carefully reviewed the PubMed database using appropriate terms. First, we summarized current knowledge of the germline RET mutations, mutation spectrum, and prevalence. We then performed a meta-analysis on the available case-control association studies for sMTC. Finally, we carried out in silico predictions of the best associated variants in the attempt to better define their role in the disease. To date, a total of 39 different RET germline mutations have been identified in fMTC families. The most affected codons are 609, 611, 618, 620 (exon 10) and 634 (exon 11), encoding for the extracellular cysteine-rich domain, and codons 768 (exon 13) and 804 (exon 14) of the intracellular tyrosine kinase domain. Six polymorphisms with at least three studies were included in the meta-analysis (A45A [rs1800858], G691S [rs1799939], L769L [rs1800861], S836S [rs1800862], S904S [rs1800863], and IVS1-126G>T [rs2565206]). The meta-analysis demonstrated a modest association of sMTC susceptibility with S836S and a strong association with the IVS1-126G>T polymorphism. Besides RET polymorphisms, we also investigated the role of a few other low-penetrance alleles of genes involved in the RET pathway or in xenobiotic metabolism, but none of these were confirmed. Thus, despite the well-known molecular basis of fMTC, the genetic variants of the sporadic form are still poorly understood, and functional analyses are needed to better understand the consequence of such RET variants and to improve our knowledge on the disease.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carcinoma, Medullary / congenital
  • Carcinoma, Medullary / genetics
  • Carcinoma, Neuroendocrine
  • Germ-Line Mutation
  • Humans
  • Multiple Endocrine Neoplasia Type 2a / genetics
  • Mutation
  • Penetrance
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret / genetics*
  • Thyroid Neoplasms / genetics*


  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-ret

Supplementary concepts

  • Familial medullary thyroid carcinoma
  • Thyroid cancer, medullary