title: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.
abstract: OBJECTIVE
  Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making.
  
  
  METHODS
  Correlative survey study of 477 MEN 2 families.
  
  
  METHODS
  Eighteen tertiary referral centers worldwide.
  
  
  METHODS
  A total of 477 independent MEN 2 families.
  
  
  METHODS
  Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family.
  
  
  RESULTS
  There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors.
  
  
  CONCLUSIONS
  This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.
authors.affiliation: Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115-6084, USA. charis_eng@macmailgw.dfci.harvard.edu
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: D
authors.initials: D
authors.lastname: Clayton
authors.forename: I
authors.initials: I
authors.lastname: Schuffenecker
authors.forename: G
authors.initials: G
authors.lastname: Lenoir
authors.forename: G
authors.initials: G
authors.lastname: Cote
authors.forename: R F
authors.initials: RF
authors.lastname: Gagel
authors.forename: H K
authors.initials: HK
authors.lastname: van Amstel
authors.forename: C J
authors.initials: CJ
authors.lastname: Lips
authors.forename: I
authors.initials: I
authors.lastname: Nishisho
authors.forename: S I
authors.initials: SI
authors.lastname: Takai
authors.forename: D J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: B G
authors.initials: BG
authors.lastname: Robinson
authors.forename: K
authors.initials: K
authors.lastname: Frank-Raue
authors.forename: F
authors.initials: F
authors.lastname: Raue
authors.forename: F
authors.initials: F
authors.lastname: Xue
authors.forename: W W
authors.initials: WW
authors.lastname: Noll
authors.forename: C
authors.initials: C
authors.lastname: Romei
authors.forename: F
authors.initials: F
authors.lastname: Pacini
authors.forename: M
authors.initials: M
authors.lastname: Fink
authors.forename: B
authors.initials: B
authors.lastname: Niederle
authors.forename: J
authors.initials: J
authors.lastname: Zedenius
authors.forename: M
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: P
authors.initials: P
authors.lastname: Komminoth
authors.forename: G N
authors.initials: GN
authors.lastname: Hendy
authors.forename: L M
authors.initials: LM
authors.lastname: Mulligan
mesh_terms: D018276:Carcinoma, Medullary / Q000235:genetics; D003062:Codon; D003545:Cysteine; D029721:Drosophila Proteins; D006627:Hirschsprung Disease / Q000235:genetics; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics
chemical_list: D003062:Codon; D029721:Drosophila Proteins; 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; D003545:Cysteine