Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population.

Background: Together single nucleotide substitutions and small insertion/deletion variants are the most common form of sequence variation in the human gene pool.

Mutations in the transcription factor p53 are among the most common genetic alterations in human cancer, and missense p53 mutations in cancer cells can lead to aggressive phenotypes. So far, only few studies investigated transcriptional reprogramming under mutant p53 expression as a means to identify deregulated targets and pathways. A review of the literature was carried out focusing on mutant p53-dependent transcriptome changes with the aims of (i) verifying whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (ii) understanding what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (iii) identifying novel candidate target genes of WT and/or mutant p53 and (iv) defining cellular pathways affected by the mutant p53-dependent gene expression reprogramming. Nearly 600 genes were consistently found upregulated or downregulated upon ectopic expression of mutant p53, regardless of the specific p53 mutation studied. Promoter analysis and the use of ChIP-seq data indicate that, for most genes, the expression changes could be ascribed to a loss both of WT p53 transcriptional activation and repressor functions. Pathway analysis indicated changes in the metabolism/catabolism of amino acids such as aspartate, glutamate, arginine and proline. Novel p53 candidate target genes were also identified, including ARID3B, ARNT2, CLMN, FADS1, FTH1, KPNA2, LPHN2, PARD6B, PDE4C, PIAS2, PRPF40A, PYGL and RHOBTB2, involved in the metabolism, xenobiotic responses and cell differentiation.

No 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 5 1.53; 95% confidence interval, CI 5 1.18-1.99; p 5 1.38 3 10 23). When we controlled for covariates, the adjusted OR was 1.48 with a 95% CI of 1.08-2.03 (p 5 8.0 3 10 23 ). 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 5 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.Thyroid tumors are relatively rare and represent about 1% of all oncological diseases. Among them, the papillary (PTC) and follicular (FTC) thyroid carcinomas (hereafter defined overall as ''differentiated thyroid carcinomas,'' DTC) are the most frequent histological type, accounting for 70-90% of cases.1,2 Epidemiological studies showed that the main risk factors for DTC are a pre-existing benign thyroid disease, [3][4][5] a positive family history of thyroid carcinoma and exposures to ionizing radiations (IRs).6-12 Hormonal factors, 13-15 elevated body mass index (BMI) 16 and a poor dietary iodine intake 17 were also hypothesized as additional risk factors. The contribution of genetic factors predisposing to thyroid cancer in familial cases was investigated and several loci were identified, including MNG1 within 14q, 18 TCO within 19p13.2,18,19 PRN1 within 1q21 20 and a 34cM region within 2q21. 21 The genetic predisposition to develop thyroid cancer was also investigated in people affected by the sporadic form. Nowadays, genome-wide association studies (GWAS) are promising in detecting new markers of susceptibility. One GWAS on thyroid cancer has been carried out in the Icelandic population and two new loci, TTF1 (14q13) and TTF2

Purpose: Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)-based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3 0 -untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU. Experimental Design: We tested 12 SNPs in the 3 0 -UTRs of five BER genes for colorectal cancer susceptibility in a case-control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).Results: SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36-0.81; P ¼ 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU-based chemotherapy (P ¼ 5.6 Â 10 À5 ). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk. Conclusions:We provide the first evidence that variations in miRNA-binding sites in BER genes 3 0 -UTR may modulate colorectal cancer prognosis and therapy response.

SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.

Mutation scanning using high-resolution melting curve analysis (HR-melt) is an effective and sensitive method to detect sequence variations. However, the presence of a common SNP within a mutation scanning amplicon may considerably complicate the interpretation of results and increase the number of samples flagged for sequencing by interfering with the clustering of samples according to melting profiles. A protocol describing simultaneous high-resolution gene scanning and genotyping has been reported. Here, we show that it can improve the sensitivity and the efficiency of large-scale case/control mutation screening. Two exons of ATM, both containing a SNP interfering with standard mutation scanning, were selected for screening of 1356 subjects from an international breast cancer genetics study. Asymmetric PCR was performed in the presence of a SNP-specific unlabeled probe. Stratification of the samples according to their probe-target melting was aided by customized HR-melt software. This approach improved identification of rare known and unknown variants, while dramatically reducing sequencing effort. It even allowed genotyping of tandem SNPs using a single probe. Hence, HR-melt is a rapid, efficient and cost-effective tool that can be used for high-throughput mutation screening for research, as well as for molecular diagnostic and clinical purposes.