title: Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.
abstract: The etiology of sporadic medullary thyroid carcinoma (sMTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic RET mutations have been described in a variable number of sMTC. So far, S836S of RET, is the only variant whose association with sMTC has been found in several European cohorts. Because RET variants seem to be associated with MTC, it is plausible that variants in genes encoding for RET coreceptors may play a role in the pathogenesis of sMTC. Recently, we described two possible low penetrance susceptibility alleles in the gene encoding RET coreceptor GFRalpha1, -193C > G and 537T > C, in a German series of sMTC. In this study, we have genotyped nine polymorphisms within GFRA1-3 genes for 51 Spanish sMTC, and 100 normal controls. Our results show that no statistical signification was found when Spanish sMTC patients were compared to controls. Taken together with the observations in the German sMTC series, the present findings suggest that GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other loci responsible for the disease with a founder effect in Germany. Alternatively, the combined observations might also suggest that, if indeed the polymorphisms are functional, the effect is small.
authors.affiliation: Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.forename: Heather
authors.initials: H
authors.lastname: Dziema
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Japón
authors.forename: Irene
authors.initials: I
authors.lastname: Marcos
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
mesh_terms: D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics*; D015331:Cohort Studies; D029721:Drosophila Proteins; D018703:Founder Effect; D005838:Genotype; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013030:Spain; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C494987:GFRA1 protein, human; C494990:GFRA2 protein, human; C494993:GFRA3 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila