Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population

Objective The molecular basis of sporadic medullary thyroid carcinoma (MTC) remains elusive. While germline gain-of-function mutations in the RET prot ooncogene cause hereditary MTC, somatic activating RET mutations and loss o f heterozygosity of markers in various chromosomal regions representing del etions of tumour suppressor genes, have been described in a variable number of sporadic MTC. A previous report suggested that the presence of a germli ne variant at RET codon 836 (S836S) was associated with the development of sporadic MTC and, furthermore, that the presence of S836S was highly correl ated with somatic RET M918T mutation in the MTC. Thus, we sought to determi ne if the S836S variant would be associated with sporadic MTC from a comple tely different population base, that of Andalucia. Design This is a case-control study to determine whether the presence of RE T germline S836S is correlated with sporadic MTC in Andalucia. Patients Thirty-two patients with sporadic MTC from the Andalucia region of Spain, serviced by our University Hospital, were ascertained throughout th e 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. Measurements 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 popula tion (18/500 chromosomes, 3.6%) differed significantly from the MTC case co hort, 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-f old risk of sporadic MTC in the Spanish population, in accordance with a pr evious study based on German cases. Our observations suggest that this phen omenon might be universal and not limited to Germany.