title: Evidences that the polymorphism Pro-282-Ala within the tumor suppressor gene WWOX is a new risk factor for differentiated thyroid carcinoma.
abstract: We report a hypothesis-driven study aimed to detect genetic markers of susceptibility to differentiated thyroid carcinomas (DTC). A large number of candidate genes were first selected through literature search (genome-wide studies were also included). To restrict the analysis to single nucleotide polymorphisms (SNPs) with a high likelihood to be associated with increased risk, each SNP must comply with several a priori hypotheses. Only one SNP, the rs3764340 encoding for the aminoacidic substitution proline-to-alanine at codon 282 of the tumor suppressor gene WWOX, passed the selection. A case-control association study was carried out, involving a total of 1,741 cases and 1,042 controls. The logistic regression analysis revealed an increased risk of DTC for the carriers of the G-allele (crude odds ratio, OR = 1.53; 95% confidence interval, CI = 1.18-1.99; p = 1.38 × 10(-3) ). When we controlled for covariates, the adjusted OR was 1.48 with a 95% CI of 1.08-2.03 (p = 8.0 × 10(-3) ). The association was confirmed after stratification for histology (for papillary thyroid carcinoma the adjusted OR was 1.43; 95% CI 1.02-2.00; p = 0.037), incident cases and smokers, but was also at the limit of statistical significance in all the other categories considered. In silico analyses showed that when alanine substitutes proline, subtle changes of the proteic structure can be predicted. These findings together with other observations from literature on human cancers and the fact that the proline at codon 282 is extremely conserved in phylogenetically distant organisms (including Drosophila) suggest that the variant allele-282 could affect the biological function of WWOX, thereby predisposing individuals to thyroid cancer.
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cancemi
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.forename: Sara
authors.initials: S
authors.lastname: Bertocchi
authors.forename: Giulia
authors.initials: G
authors.lastname: Tarrini
authors.forename: Irene
authors.initials: I
authors.lastname: Spitaleri
authors.forename: Monica
authors.initials: M
authors.lastname: Cipollini
authors.forename: Debora
authors.initials: D
authors.lastname: Landi
authors.forename: Sonia
authors.initials: S
authors.lastname: Garritano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pellegrini
authors.forename: Alfonso
authors.initials: A
authors.lastname: Cristaudo
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinchera
authors.forename: Roberto
authors.initials: R
authors.lastname: Barale
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D016153:Genes, Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human