title: Role of RET genetic variants in MEN2-associated pheochromocytoma.
abstract: BACKGROUND
  RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma.
  
  
  OBJECTIVE
  To investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients.
  
  
  METHODS
  The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan-Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance.
  
  
  RESULTS
  A total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4-5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24-16.03); P<0.001).
  
  
  CONCLUSIONS
  RET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Débora Rodrigues
authors.initials: DR
authors.lastname: Siqueira
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Lucieli
authors.initials: L
authors.lastname: Ceolin
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Carla Vaz
authors.initials: CV
authors.lastname: Ferreira
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Mírian
authors.initials: M
authors.lastname: Romitti
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Silvana Cavalcante
authors.initials: SC
authors.lastname: Maia
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Léa Maria Zanini
authors.initials: LM
authors.lastname: Maciel
authors.affiliation: Endocrine DivisionThyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BrazilDepartment of Internal MedicineSchool of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil almaia@ufrgs.br.
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Maia
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D055815:Young Adult
chemical_list: D051096:Proto-Oncogene Proteins c-ret