Incidence rates of colorectal cancer vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries2-5. The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

• Publication type
• Journal Article MeSH

Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

• Publication type
• Journal Article MeSH
• Preprint MeSH

OBJECTIVES: Although sarcopenia is recognized as one of the risk factors for increased morbidity after resection for colorectal cancer, the question of the most appropriate way to identify and quantify it is still unresolved. MATERIAL AND METHODS: This is a retrospective unicentric study following patients undergoing elective resection of the rectum for carcinoma with available staging computed tomography (CT) of the trunk. Psoas muscle density (PMD) and its area relative to patient height psoas muscle index (PMI) at the level of inferior vertebral end plate of third lumbar vertebra (L3) were assessed using an initial staging CT scan of the trunk. Post-operative complications, evaluated according to the Clavien-Dindo classification, and blood samples on post-operative days (POD) 3 and 5 were also recorded in the study population. Patients were divided into groups with complicated and uncomplicated post-operative course, and observed parameters were then statistically compared. RESULTS: The correlation of PMI values with the development of post-operative complications was not confirmed in a data set of 206 patients. PMD values were found to be borderline statistically significant in patients with complicated post-operative course, while in the group of patients with severe complications (Clavien-Dindo III-IV), there was no statistically significant difference in PMI or PMD values. The same results were obtained when comparing patients with anastomotic leak (AL). It was confirmed that operations on the lower rectum are riskier for the development of post-operative complications. The secondary objective of our study regarding serum C-reactive protein (CRP) levels of 3rd and 5th POD gave us the answer in the form of cutoff values of 115.7 mg/L (3rd POD) and 76 mg/L (5th POD). CONCLUSION: PMD appears to be a promising tool for predicting post-operative morbidity in patients after rectal resection, but a clear consensus on the method of measurement, interpretation of results and cutoff values is needed. Lower rectal resections are burdened with a higher risk of post-operative complications, especially AL. Monitoring of CRP levels remains an important marker in the prediction of AL due to its negative predictive value.

• Keywords
• Complications, Psoas densitometry, Psoas volumometry, Rectal cancer, Sarcopenia,
• Publication type
• Journal Article 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.

• Keywords
• GWAS, Mendelian randomization, early-onset colorectal cancer, genetics, risk factors,
• MeSH
• Genome-Wide Association Study * MeSH
• Adult MeSH
• Genetic Predisposition to Disease * MeSH
• Polymorphism, Single Nucleotide MeSH
• Colorectal Neoplasms * genetics   epidemiology   MeSH
• Humans MeSH
• Mendelian Randomization Analysis * MeSH
• Risk Factors MeSH
• Case-Control Studies MeSH
• Age of Onset MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

BACKGROUND: Coverage by examinations is a crucial indicator of the future impact on the burden of colorectal cancer (CRC). The study aimed to evaluate coverage by examinations associated with CRC screening and early cancer detection of CRC in the Czech Republic. The burden of CRC was also assessed. METHODS: The novel nationwide administrative registry with individual data (period 2010-19) was used to evaluate coverage by examinations for screening faecal occult blood test and colonoscopy. In the second step, additional examinations for early CRC detection were included in the coverage calculation (complete coverage). Age-specific trends in CRC incidence (period 1977-2018) were investigated using Joinpoint regression. RESULTS: Coverage by screening examinations within recommended interval was around 30%. Complete coverage reached >37% and >50% at the 3-year interval. The coverage by examinations for the non-screening population aged 40-49 years was almost 4% and 5% (most of them were colonoscopies) at the 3-year interval. In age groups aged ≥50 years, we observed a significant annual decline, especially in the 50-69 age group, with recent annual decreases reaching up to 5-7%. The change in trend and the recent decline were also observed in the age group 40-49. CONCLUSIONS: More than half of the target screening population was covered by examinations potentially associated with early detection and subsequent treatment of colorectal neoplasms. The substantial coverage by potentially prophylactic examinations might be an explanation for the considerable decrease in CRC incidence.

• MeSH
• Early Detection of Cancer * MeSH
• Colorectal Neoplasms * diagnosis   epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Occult Blood MeSH
• Mass Screening MeSH
• Registries MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH

The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.

• Keywords
• EpCAM, colorectal carcinoma, desaturation, epithelial cells, fatty acid synthesis, lipidomics, lysophospholipids, phospholipids,
• MeSH
• Adenocarcinoma enzymology   genetics   metabolism   MeSH
• Fatty Acid Desaturases genetics   metabolism   MeSH
• Fatty Acid Elongases genetics   metabolism   MeSH
• Epithelial Cells enzymology   metabolism   MeSH
• Phospholipids metabolism   MeSH
• Humans MeSH
• Lipidomics MeSH
• Lipogenesis MeSH
• Fatty Acids metabolism   MeSH
• Lipid Metabolism * MeSH
• Colonic Neoplasms enzymology   genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Stearoyl-CoA Desaturase genetics   metabolism   MeSH
• Fatty Acid Synthases genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fatty Acid Desaturases MeSH
• Fatty Acid Elongases MeSH
• ELOVL5 protein, human MeSH Browser
• FADS2 protein, human MeSH Browser
• Phospholipids MeSH
• Fatty Acids MeSH
• Stearoyl-CoA Desaturase MeSH
• Fatty Acid Synthases MeSH