Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

• MeSH
• biologická variabilita populace genetika   MeSH
• DNA modifikační methylasy genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• dospělí MeSH
• enzymy opravy DNA genetika   MeSH
• genetická predispozice k nemoci * MeSH
• hodnocení rizik MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kolon patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• MutL homolog 1 genetika   MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory rekta genetika   patologie   MeSH
• nádory tračníku genetika   patologie   MeSH
• oprava DNA genetika   MeSH
• registrace statistika a číselné údaje   MeSH
• rektum patologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of the mesothelin (MSLN) gene could affect the levels of SMRP. OBJECTIVES: To focus on SNPs located within MSLN promoter as possible critical genetic variables in determining SMRP levels. METHODS: The association between SMRP and SNPs was tested in 689 non-MPM subjects and 70 patients with MPM. Reporter plasmids carrying the four most common haplotypes were compared in a dual luciferase assay, and in silico analyses were performed to investigate the putative biological role of the SNPs. RESULTS: We found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (in strong linkage disequilibrium with rs2235504) and rs2235503 in non-MPM subjects. Inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the group with MPM showed the same trend of association. According to the in vitro luciferase study, rs3764247 itself had a functional role. In silico approaches showed that the binding sites for transcription factors such as Staf and ZNF143 could be affected by this SNP. The other SNPs were shown to interact with each other in a more complex way. CONCLUSIONS: These data support the suggestion that SMRP performance is affected by individual (ie, genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.

• MeSH
• alely MeSH
• analýza rozptylu MeSH
• azbest škodlivé účinky   MeSH
• genotyp MeSH
• GPI-vázané proteiny krev   genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• luciferasy MeSH
• mezoteliom krev   diagnóza   genetika   MeSH
• nádorové biomarkery krev   genetika   MeSH
• nádory plic krev   diagnóza   genetika   MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Itálie MeSH