title: Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.
abstract: OBJECTIVE
  The molecular basis of sporadic medullary thyroid carcinoma (MTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic activating RET mutations and loss of heterozygosity of markers in various chromosomal regions representing deletions of tumour suppressor genes, have been described in a variable number of sporadic MTC. A previous report suggested that the presence of a germline variant at RET codon 836 (S836S) was associated with the development of sporadic MTC and, furthermore, that the presence of S836S was highly correlated with somatic RET M918T mutation in the MTC. Thus, we sought to determine if the S836S variant would be associated with sporadic MTC from a completely different population base, that of Andalucia.
  
  
  METHODS
  This is a case-control study to determine whether the presence of RET germline S836S is correlated with sporadic MTC in Andalucia.
  
  
  METHODS
  Thirty-two patients with sporadic MTC from the Andalucia region of Spain, serviced by our University Hospital, were ascertained throughout the period 1995-99. Sporadic MTC was defined as a lack of personal or family history suggestive of multiple endocrine neoplasia type 2 (MEN 2) and lack of germline RET mutations which define any MEN 2 subtype. A region and race matched cohort of 250 controls was also obtained.
  
  
  METHODS
  The frequency of the S836S allele was determined in cases and controls and compared using the standard chi-squared statistic and Fisher's exact test.
  
  
  RESULTS
  The polymorphic allele frequency at codon 836 in the control population (18/500 chromosomes, 3.6%) differed significantly from the MTC case cohort, 9.3% of case chromosomes (six of 64 alleles, Fisher's exact test, two-tailed, P = 0.043).
  
  
  CONCLUSIONS
  Germline RET S836S variant is associated with a two- to three-fold risk of sporadic MTC in the Spanish population, in accordance with a previous study based on German cases. Our observations suggest that this phenomenon might be universal and not limited to Germany.
authors.affiliation: Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
authors.forename: G
authors.initials: G
authors.lastname: Antiñolo
authors.forename: R M
authors.initials: RM
authors.lastname: Fernández
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: I
authors.initials: I
authors.lastname: Marcos
authors.forename: S
authors.initials: S
authors.lastname: Borrego
mesh_terms: D000328:Adult; D000368:Aged; D018276:Carcinoma, Medullary / Q000235:genetics*; D016022:Case-Control Studies; D029721:Drosophila Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D013030:Spain; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: 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