title: Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A.
abstract: Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series.
authors.affiliation: Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge,Worts Causeway, Cambridge CB1 8RN, UK.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.forename: Arancha
authors.initials: A
authors.lastname: Cebrian
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Patricia
authors.initials: P
authors.lastname: Niccoli-Sire
authors.forename: Karl-Axel
authors.initials: KA
authors.lastname: Svensson
authors.forename: Stephane
authors.initials: S
authors.lastname: Pinson
authors.forename: Jean
authors.initials: J
authors.lastname: Leyland
authors.forename: Joanne
authors.initials: J
authors.lastname: Whittaker
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
mesh_terms: D000328:Adult; D017668:Age of Onset; D018276:Carcinoma, Medullary / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008024:Ligands; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011956:Receptors, Cell Surface; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human