Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma

Oncogene. 2001 Apr 19;20(17):2161-70. doi: 10.1038/sj.onc.1204289.


In contrast to the hereditary form of medullary thyroid carcinoma (MTC), little is known about the etiology of sporadic MTC. Somatic gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, are found in an average of 40% of sporadic MTC. We analysed 31 sporadic MTC for somatic and germline variants in GFRA1, GFRA2 and GFRA3 which encode the co-receptors of RET. Although there were no somatic mutations in any of the three genes, a sequence variant (-193C>G) in the 5'-UTR of GFRA1 was found in 15% of cases. Three patients were heterozygous (het); another three patients homozygous (hom) for the G variant. The G allele was not observed in 31 race-matched normal controls. Hence, the relative frequency of this variant in sporadic MTC cases and controls differed significantly (P<0.05). Since this variant lies in the 5' UTR, likely at the transcriptional start site, we analysed for differential expression of GFRalpha-1 at the transcript and protein levels. At the mRNA level, GFRA1 was over-expressed in tumors harboring the rare variant (P=0.06). The presence of the G polymorphic allele seemed to be associated with increased expression by immunostaining for GFRalpha-1. Interestingly, cytoplasmic staining was stronger in intensity for het patients and nuclear staining predominant in hom cases. In conclusion, mutation analysis of GFRA1, GFRA2 and GFRA3 revealed over-representation of a rare variant in GFRA1 (-193C>G) in the germline of sporadic MTC cases. Our data suggest that the mechanism is related to over-expression of GFRalpha-1 and differential subcellular compartmentalization but the precise mechanism as to how it acts as a low penetrance susceptibility allele for the development of sporadic MTC remains to be elucidated.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carcinoma, Medullary / genetics*
  • Carcinoma, Medullary / metabolism
  • DNA Mutational Analysis
  • Drosophila Proteins*
  • Germ-Line Mutation*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Humans
  • Immunohistochemistry
  • Penetrance
  • Polymerase Chain Reaction
  • Protein Isoforms
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / biosynthesis
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism


  • Drosophila Proteins
  • GFRA1 protein, human
  • GFRA3 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • MAS1 protein, human
  • Protein Isoforms
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila