Colorectal cancer (CRC) develops as a consequence of inherited multiple low-risk variants in concurrence of environmental factors. Nutrition and intestinal microbiota exert an effect on DNA damage accumulation and its repair (maintaining universal genomic stability and preserves cellular functions), intestinal metabolism, immunological activity and substantially affect the efficacy of chemotherapy. Integrated studies should unveil in humans the role of A) Taste perception, intestinal microbiota, DNA damage and repair in CRC risk (CRC patients vs. control individuals); B) Intestinal microbiota, DNA damage and repair as prognostic markers of CRC progression, treatment efficacy and survival. Monitoring of taste perception and intestinal microenvironment with simultaneous determinations of DNA damage response and repair in cancer patients represent substantial novel contribution. Our project further aims to integrate above parameters into the prognostic and therapeutical considerations, which ultimately result in individually tailored therapy and improved quality of the life.

Nádory tlustého střeva a konečníku (CRC) vznikají v důsledku souhry četných genových variant s faktory životního prostředí. Výživa a střevní mikroflóra významně ovlivňují akumulaci poškození DNA, jejich opravu (udržující genomovou stabilitu a buněčné funkce), jakož i střevní metabolismus, imunologickou aktivitu, a hrají výraznou roli v odpovědi na chemoterapii. V našich studiích se budeme zabývat A) Vnímáním chuti, střevní mikroflórou, poškozením DNA a kapacitou DNA oprav jako faktorů ovlivňujících vznik CRC (pacienti versus kontrolní osoby); B) Střevní mikroflórou, poškozením DNA a kapacitou DNA oprav jako prognostickými znaky progrese CRC, účinnosti terapie a přežívání. Monitorování chuťového vnímání a střevní mikroflóry při současném stanovování kapacity oprav DNA poškození u pacientů s CRC představuje zásadně nový přístup. V naší studii dále zamýšlíme integrovat sledované parametry do prognostických a terapeutických úvah, jež v konečném důsledku přispějí k individualizované terapii a zlepšené kvalitě života pacientů.

• MeSH
• chirurgie trávicího traktu MeSH
• geny rRNA MeSH
• kolorektální nádory MeSH
• lidé MeSH
• messenger RNA MeSH
• odběr tkání a orgánů metody   MeSH
• polymerázová řetězová reakce MeSH
• preanalytická fáze MeSH
• reprodukovatelnost výsledků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• onkologie
• gastroenterologie
• experimentální medicína
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

• MeSH
• dospělí MeSH
• genetická epistáze * MeSH
• genotypizační techniky MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kinasa I-kappa B genetika   MeSH
• kohortové studie MeSH
• kolon diagnostické zobrazování   patologie   MeSH
• kolonoskopie MeSH
• kolorektální nádory diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nukleotidyltransferasy genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• rektum diagnostické zobrazování   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• studie případů a kontrol MeSH
• toll-like receptor 3 genetika   MeSH
• výpočetní biologie MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

• MeSH
• anamnéza MeSH
• celogenomová asociační studie MeSH
• datové soubory jako téma MeSH
• genetická predispozice k nemoci * MeSH
• genotypizační techniky MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• kolorektální nádory genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• mutační rychlost MeSH
• rizikové faktory MeSH
• sekvenování celého genomu MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• životní styl MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

• MeSH
• Asijci genetika   MeSH
• celogenomová asociační studie MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 genetika   MeSH
• mutace INDEL MeSH
• rizikové faktory 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 MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Čína MeSH
• Japonsko MeSH
• Korejská republika MeSH

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.

• MeSH
• chromozomální nestabilita MeSH
• homeostáza telomer genetika   MeSH
• kolorektální nádory farmakoterapie   genetika   metabolismus   patologie   MeSH
• kontrolní body buněčného cyklu genetika   MeSH
• lidé MeSH
• nádorová transformace buněk genetika   metabolismus   MeSH
• oprava DNA genetika   MeSH
• stárnutí buněk genetika   MeSH
• telomerasa genetika   metabolismus   MeSH
• telomery metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The circulating human transcriptome, which includes both coding and non-coding RNA (ncRNA) molecules, represents a rich source of potential biomarkers for colorectal cancer (CRC) that has only recently been explored. In particular, the release of RNA-containing extracellular vesicles (EVs), in a multitude of different in vitro cell systems and in a variety of body fluids, has attracted wide interest. The role of RNA species in EVs is still not fully understood, but their capacity to act as a form of distant communication between cells and their higher abundance in association with cancer demonstrated their relevance. In this review, we report the evidence from both in vitro and human studies on microRNAs (miRNAs) and other ncRNA profiles analysed in EVs in relation to CRC as diagnostic, prognostic and predictive markers. The studies so far highlighted that, in exosomes, the most studied category of EVs, several miRNAs are able to accurately discriminate CRC cases from controls as well as to describe the progression of the disease and its prognosis. Most of the time, the in vitro findings support the miRNA profiles detected in human exosomes. The expression profiles measured in exosomes and other EVs differ and, interestingly, there is a variability of expression also among different subsets of exosomes according to their proteic profile. On the other hand, evidence is still limited for what concerns exosome miRNAs as early diagnostic and predictive markers of treatment. Several other ncRNAs that are carried by exosomes, mostly long ncRNAs and circular RNAs, seem also to be dysregulated in CRC. Besides various technical challenges, such as the standardisation of EVs isolation methods and the optimisation of methodologies to characterise the whole spectrum of RNA molecules in exosomes, further studies are needed in order to elucidate their relevance as CRC markers.

• MeSH
• exozómy genetika   metabolismus   MeSH
• extracelulární vezikuly genetika   metabolismus   MeSH
• kolorektální nádory krev   diagnóza   genetika   metabolismus   MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nekódující RNA genetika   metabolismus   MeSH
• progrese nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

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

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

• MeSH
• celogenomová asociační studie metody   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kolorektální nádory genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• rizikové faktory MeSH
• RNA dlouhá nekódující genetika   MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

DNA repair, a complex biological process, ensures genomic integrity. Alterations in DNA repair, occurring in many cancers, contribute to the accumulation of mutations in the genome, resulting in genomic instability and cancer progression. DNA repair also plays a substantial role in response to chemotherapeutics: rapidly dividing colon cancer cells, vulnerable to DNA-damaging agents and overcoming DNA repair, undergo cell death. DNA repair capacity represents a complex biomarker, integrating gene variants, gene expressions, the stability of gene products, the effect of inhibitors/stimulators, lifestyle and environmental factors. Here, we discuss DNA repair capacity in sporadic colon cancer, a frequent malignancy worldwide, in relation to tumor heterogeneity, prognosis and prediction, measurements in surrogate and target tissues and suggest important tasks to be addressed.

• MeSH
• buněčná smrt účinky léků   MeSH
• epigeneze genetická genetika   MeSH
• lidé MeSH
• mutace MeSH
• nádory tračníku farmakoterapie   genetika   patologie   MeSH
• nestabilita genomu účinky léků   genetika   MeSH
• oprava DNA účinky léků   MeSH
• poškození DNA účinky léků   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

There is increasing evidence indicating a role for Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) development and prognosis. This study evaluated F. nucleatum as a prognostic biomarker, by assessing its association with post-diagnosis survival from CRC. From September 2008 to April 2012 CRC patients (n = 190) were recruited from three hospitals within the Czech Republic. F. nucleatum DNA copies were measured in adjacent non-malignant and colorectal tumor tissues using quantitative real-time PCR. Cox Proportional Hazards (HR) models were applied to evaluate the association between F. nucleatum DNA and overall survival, adjusting for key confounders. Risk prediction modeling was conducted to evaluate the ability to predict survival based on F. nucleatum status. High, compared with low, levels of F. nucleatum in colorectal tumor tissues were associated with poorer overall survival (adjusted HR 1.68, 95% CI 1.02-2.77), which was slightly attenuated after additional adjustment for microsatellite instability status. However, inclusion of F. nucleatum in risk prediction models did not improve the ability to identify patients who died beyond known prognostic factors such as disease pathology staging. Although the increased presence of F. nucleatum was associated with poorer prognosis in CRC patients, this may have limited clinical relevance as a prognostic biomarker.

• MeSH
• analýza přežití MeSH
• biologické markery analýza   MeSH
• DNA bakterií analýza   MeSH
• Fusobacterium nucleatum genetika   MeSH
• hodnocení rizik MeSH
• infekce bakteriemi rodu Fusobacterium mikrobiologie   MeSH
• kohortové studie MeSH
• kolorektální nádory mortalita   patologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH