Mucins and their glycosylation have been suggested to play an important role in colorectal carcinogenesis. We examined potentially functional genetic variants in the mucin genes or genes involved in their glycosylation with respect to colorectal cancer (CRC) risk and clinical outcome. We genotyped 23 single nucleotide polymorphisms (SNPs) covering 123 SNPs through pairwise linkage disequilibrium (r2>0.80) in the MUC1, MUC2, MUC4, MUC5AC, MUC6, and B3GNT6 genes in a hospital-based case-control study of 1532 CRC cases and 1108 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 672 patients. Among patients without distant metastasis at the time of diagnosis, two MUC4 SNPs, rs3107764 and rs842225, showed association with overall survival (HR 1.40, 95%CI 1.08-1.82, additive model, log-rank p = 0.004 and HR 0.64, 95%CI 0.42-0.99, recessive model, log-rank p = 0.01, respectively) and event-free survival (HR 1.31, 95%CI 1.03-1.68, log-rank p = 0.004 and HR 0.64, 95%CI 0.42-0.96, log-rank p = 0.006, respectively) after adjustment for age, sex and TNM stage. Our data suggest that genetic variation especially in the transmembrane mucin gene MUC4 may play a role in the survival of CRC and further studies are warranted.

• MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• genotyp MeSH
• glykosylace MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory genetika   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mucin 4 genetika   metabolismus   MeSH
• muciny genetika   metabolismus   MeSH
• nádorové biomarkery genetika   MeSH
• nádory tračníku genetika   mortalita   patologie   MeSH
• přežití bez známek nemoci MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• MUC4 protein, human MeSH Prohlížeč
• mucin 4 MeSH
• muciny MeSH
• nádorové biomarkery MeSH

BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

• MeSH
• familiární adenomatózní polypóza genetika   MeSH
• genetická predispozice k nemoci * MeSH
• genetická vazba MeSH
• genotyp MeSH
• homozygot MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 1 genetika   MeSH
• mapování chromozomů MeSH
• messenger RNA metabolismus   MeSH
• mikrosatelitní repetice MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• prekancerózy genetika   metabolismus   MeSH
• proteiny aktivující GTPasu genetika   metabolismus   MeSH
• receptory aromatických uhlovodíků - jaderný translokátor genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ARNT protein, human MeSH Prohlížeč
• messenger RNA MeSH
• nádorové proteiny MeSH
• proteiny aktivující GTPasu MeSH
• receptory aromatických uhlovodíků - jaderný translokátor MeSH