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

Oncogene volume 20, pages 2161–2170 (2001)Cite this article

Abstract

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 GFRα-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 GFRα-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 GFRα-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.

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Acknowledgements

O Gimm thanks Dr Stephan M Tanner for helpful discussions. The authors acknowledge Kathrin Hammje, Marion Sitte and Irene Schwarz for technical assistance and Terry Bradley for graphics advice and assistance. This study was partially funded by 1R01HD39058-01 from the National Institutes of Health (to C Eng) and P30CA16058 from the National Cancer Institute (to Ohio State University Comprehensive Cancer Center).

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Authors and Affiliations

  1. Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Centre, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, 43210, Ohio, OH, USA

    Oliver Gimm, Heather Dziema, Jessica Brown & Charis Eng

  2. Department of General Surgery, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany

    Cuong Hoang-Vu & Henning Dralle

  3. Institute of Pathology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany

    Raoul Hinze

  4. Department of Pathology, Queen's University, Kingston, ON K7L 3NR, Ontario, Canada

    Lois M Mulligan

  5. Department of Paediatrics, Queen's University, Kingston, ON K7L 3NR, Ontario, Canada

    Lois M Mulligan

  6. Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge, CB2 2QQ, UK

    Charis Eng

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Gimm, O., Dziema, H., Brown, J. et al. Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma. Oncogene 20, 2161–2170 (2001). https://doi.org/10.1038/sj.onc.1204289

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