Evidences that the polymorphism Pro-282-Ala within the tumor suppressor gene WWOX is a new risk factor for differentiated thyroid carcinoma.

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.

Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mostly attributable to asbestos exposure. Many polymorphic genes encoding for xenobiotic and oxidative metabolism enzymes (XME) or involved in genome stability (GS) can modulate individual MPM risk in exposed populations. An association study was carried out in a case-control setting including 119 MPM patients and two groups of referent subjects (104 with and 695 without documented asbestos exposure). Forty-eight polymorphisms in XME genes and 75 in GS-genes were evaluated. Statistical analysis revealed some significant associations of studied polymorphisms with MPM risk, but most of them disappeared after applying Bonferroni correction (new threshold for statistical significance: p=4.07 x 10(-4)). On the other hand, the nucleotidic change 282C>T within NAT2 held the statistical significance (OR=3.54; 95% CI 1.75-7.16; p=0.0002), reinforcing existing evidences that describe genetic polymorphisms of NAT2 possibly involved in the etiology of the MPM.