title: RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation.
abstract: OBJECTIVE
  Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634.
  
  
  METHODS
  The study was retrospective and multicentric.
  
  
  METHODS
  We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6±6.9 years (1-32).
  
  
  RESULTS
  Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001).
  
  
  CONCLUSIONS
  Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain nvaldes@hca.es.
authors.forename: Nuria
authors.initials: N
authors.lastname: Valdés
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Mesa
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Casterás
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Alcázar
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lamas
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Tébar
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gaztambide
authors.affiliation: Department of Endocrinology and NutritionHospital Universitario Central de Asturias, Avenida de Roma s/n, E-33011 Oviedo, Asturias, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen del Rocío, Sevilla, SpainDepartment of Endocrinology and NutritionHospital de Vall d'Hebron, Barcelona, SpainDepartment of Endocrinology and NutritionHospital Severo Ochoa, Madrid, SpainDepartment of Endocrinology and NutritionComplejo Hospitalario Universitario de Albacete, Albacete, SpainDepartment of Endocrinology and NutritionHospital Universitario Virgen de la Arrixaca, Murcia, SpainEndocrinology and Diabetes Research GroupDepartment of Endocrinology and NutritionHospital Universitario de Cruces, Barakaldo, SpainDepartment of EndocrinologyComplejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Forga
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret