title: Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal.
abstract: OBJECTIVE
  Medullary thyroid carcinoma (MTC) occurs both sporadically and in the context of autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), which are caused by activating germline mutations in the RET proto-oncogene. The aim of this study was to characterize the RET mutational spectrum in MEN2 families and apparently sporadic MTC (AS-MTC) cases originating from the central region of Portugal.
  
  
  METHODS
  We studied a total of 82 individuals (64 affected and 18 family members), comprising five MEN2 families (four MEN2A and one MEN2B), as well as 53 AS-MTC cases. RET germline mutations were screened using PCR-DNA sequencing, SSCP and RFLP. The haplotypes associated with recurrent mutations were determined by fragment analysis of microsatellite markers, and by RFLP, in the case of intragenic polymorphisms.
  
  
  RESULTS
  Frequency of the Cys611Tyr (TGC-TAC) mutation was significantly increased in this region of Portugal, due to the fact that three apparently unrelated MEN2A/FMTC families, out of the five in which mutations were identified, harboured this specific mutation. Haplotype analysis revealed that a common haplotype was shared between two of these three families. We have also characterized a novel RET mutation, Arg886Trp, located in the tyrosine kinase domain, which was found in an AS-MTC case.
  
  
  CONCLUSIONS
  There are regional specificities in the relative frequency of RET mutations, which are consistent with a cluster-like distribution of specific disease-causing mutations, as a result of the inheritance of a shared haplotype. These data, along with the finding of a novel RET mutation (Arg886Trp), have important implications towards facilitating and improving the molecular diagnosis of hereditary MTC on a regional basis.
authors.affiliation: Molecular Pathology Laboratory, Regional Centre of Oncology of Coimbra, Portuguese Institute of Oncology, Coimbra, Portugal. upmolecular@croc.min-saude.pt
authors.forename: Hugo João
authors.initials: HJ
authors.lastname: Prazeres
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues
authors.forename: Paulo
authors.initials: P
authors.lastname: Figueiredo
authors.forename: Plamen
authors.initials: P
authors.lastname: Naidenov
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bugalho
authors.forename: Manuela
authors.initials: M
authors.lastname: Lacerda
authors.forename: Beatriz
authors.initials: B
authors.lastname: Campos
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Martins
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011174:Portugal; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D016415:Sequence Alignment; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret