A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.

• Klíčová slova
• familial colorectal cancer, germline variant, multiple primaries, whole‐exome sequencing,
• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• oprava DNA genetika   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• senioři MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

• Klíčová slova
• GWAS, Mendelian randomization, early-onset colorectal cancer, genetics, risk factors,
• MeSH
• celogenomová asociační studie * MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * genetika   epidemiologie   MeSH
• lidé MeSH
• mendelovská randomizace * MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

OBJECTIVE: To highlight the issue of diagnostics and treatment management in colorectal cancer of pregnant women. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Pardubice Hospital. CASE REPORT: We present a case of a 24-year-old secundigravida, diagnosed as colorectal cancer in week 34 of pregnancy, manifesting as a diarrhoea and a stomach ache. The diagnosis was made in an advanced stage due to underestimation of clinical symptoms. CONCLUSION: The diagnosis of the colorectal cancer in pregnancy can be difficult because the presenting symptoms are easily attributable to pregnancy. Therefore the advanced disease is diagnosed more frequently in pregnant patients than in the general population. Colorectal cancer should be managed by multidisciplinary team with regard to gestation.

• Klíčová slova
• cesarean section, colorectal cancer, diarrhoea in pregnancy, pregnancy,
• MeSH
• kolorektální nádory * diagnóza   terapie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové komplikace v těhotenství * diagnóza   terapie   MeSH
• průjem MeSH
• staging nádorů MeSH
• těhotenství MeSH
• výsledek těhotenství MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• dědičné nepolypózní kolorektální nádory * genetika   MeSH
• kolorektální nádory * genetika   MeSH
• lidé MeSH
• Check Tag
• lidé 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, Non-P.H.S. MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

BACKGROUND AND OBJECTIVES: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status. METHODS: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex. RESULTS: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60-75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89-3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67-3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28-2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72-3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05-2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63-3.42, p = 0.005), respectively. CONCLUSION: In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.

• Klíčová slova
• colorectal cancer, non‐colorectal malignancy, sporadic deficient mismatch repair,
• MeSH
• incidence MeSH
• kolorektální nádory * genetika   patologie   epidemiologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• MutL homolog 1 genetika   MeSH
• následné studie MeSH
• oprava chybného párování bází DNA * MeSH
• prognóza MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Švédsko epidemiologie   MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• MLH1 protein, human MeSH Prohlížeč
• MutL homolog 1 MeSH
• protoonkogenní proteiny B-Raf MeSH

Cancer is one of the most important causes of death throughout the world, and the mortality rate is increasing significantly due to the aging of the population. One of the most common types of cancer is colorectal cancer (CRC). Human microbial ecosystems use metabolism to make important impacts on the body physiology. An intensive literature review was made to investigate the correlations between human gut microbiota and the incidence of CRC. The results of these studies show that there are differences in the composition of microbiota between CRC patients and normal people and the microorganisms in CRC patients are very different from healthy individuals. Therefore, changes in the microbiome can be used as a biomarker for the early detection of CRC. On the other hand, the intestinal flora is may be act as a powerful weapon against CRC in the future.

• Klíčová slova
• Bacteriology, Colorectal cancer, Gastrointestinal, Microbiome, Vaccine,
• MeSH
• kolorektální nádory * diagnóza   MeSH
• lidé MeSH
• mikrobiota * MeSH
• střevní mikroflóra * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND & AIMS: Patient-derived organoid cancer models are generated from epithelial tumor cells and reflect tumor characteristics. However, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we developed a colorectal cancer organoid model that incorporates matched epithelial cells and stromal fibroblasts. METHODS: Primary fibroblasts and tumor cells were isolated from colorectal cancer specimens. Fibroblasts were characterized for their proteome, secretome, and gene expression signatures. Fibroblast/organoid co-cultures were analyzed by immunohistochemistry and compared with their tissue of origin, as well as on gene expression levels compared with standard organoid models. Bioinformatics deconvolution was used to calculate cellular proportions of cell subsets in organoids based on single-cell RNA sequencing data. RESULTS: Normal primary fibroblasts, isolated from tumor adjacent tissue, and cancer associated fibroblasts retained their molecular characteristics in vitro, including higher motility of cancer associated compared with normal fibroblasts. Importantly, both cancer-associated fibroblasts and normal fibroblasts supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. Organoids grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared with mono-cultures and closely resembled the in vivo tumor morphology. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by considerably deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. Thrombospondin-1 was identified as a critical factor for fibroblast invasiveness. CONCLUSION: We developed a physiological tumor/stroma model, which will be vital as a personalized tumor model to study disease mechanisms and therapy response in colorectal cancer.

• Klíčová slova
• Cancer, Co-cultures, Colorectal Cancer, Fibroblasts, Organoids,
• MeSH
• fibroblasty asociované s nádorem * metabolismus   MeSH
• fibroblasty metabolismus   MeSH
• kokultivační techniky MeSH
• kolorektální nádory * patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• organoidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: For the last three decades, although colorectal cancer incidence has been decreasing in those over 50 years of age, it has been increasing in those under 50 included in the pre-screening group (PSG). The present study aims to explain the screening-related factors and compliance of individuals in PSG who are not included in the colorectal cancer screening programme. METHODS: This cross-sectional study was conducted with a total of 323 participants, 143 of whom were from the pre-screening group (40-49 years), and 180 from the screening included group (SIG) (50-70 years). RESULTS: Individuals included in PSG were more likely to have accepted that both faecal occult blood test (FOBT) (2.23 ± 1.22 vs. 1.89 ± 1.33, p = 0.018) and colonoscopy (2.37 ± 0.97 vs. 2.02 ± 1.14, p = 0.003) were useful and suitable screening tests in colorectal cancer. Adequate health literacy (OR = 4.3, 95% CI: 1.8-10.0, p = 0.001) and better education level (OR = 3.3, 95% CI: 1.3-8.4, p = 0.010) were factors of increased knowledge of colorectal cancer screening. CONCLUSIONS: The findings show that PSG has different characteristics than SIG and may be more fitting in the colorectal cancer screening programme if included.

• Klíčová slova
• cancer screening tests, colorectal cancer, early diagnosis of cancer, health literacy, screening,
• MeSH
• časná detekce nádoru * MeSH
• kolonoskopie MeSH
• kolorektální nádory * diagnóza   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• plošný screening MeSH
• průřezové studie MeSH
• stupeň vzdělání MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

There is the increase in colorectal cancer incidence in Japan. The increase in the rate of colon cancer compared with rectal cancer was noticed. The proximal migration of the tumor site from the left colon to right colon is shown in the study. The evident shift toward earlier stage was clearly revealed. According to the extended lymph node resection, the improvement of overall 5-year survival rate from 55% to 69% is important trend.

• MeSH
• kolorektální nádory epidemiologie   patologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Japonsko epidemiologie   MeSH

Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

• Klíčová slova
• DNMT inhibitors, colorectal cancer, methylation, therapy,
• MeSH
• kolorektální nádory genetika   terapie   MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH