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Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC‐associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor‐free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early‐ and late‐stage cancer and could be validated in independent patient and control populations ( N  = 335) from different countries. CRC‐associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor‐related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism. Synopsis Metagenomic profiling of fecal samples from colorectal cancer (CRC) patients in comparison with tumor‐free controls reveals strong associations between the gut microbiota and cancer. Their potential for noninvasive cancer screening is explored systematically. A classification model based on gut microbial marker species distinguishes CRC patients from controls with similar accuracy as the fecal occult blood test (FOBT), routinely used for clinical screening. Combining metagenomic data with the FOBT leads to a relative improvement in sensitivity of > 45% over the FOBT alone at identical specificity. Detection accuracy of the metagenomic test is maintained in an independent study population and is still high for alternative microbiome readouts, such as the abundance of 16S rRNA OTUs or families of functionally related genes. Functional metagenomic analysis indicates an increased potential of CRC‐associated microbiota for degradation of host glycans and amino acids and for pro‐inflammatory lipopolysaccharide metabolism. Graphical Abstract Metagenomic profiling of fecal samples from colorectal cancer (CRC) patients in comparison with tumor‐free controls reveals strong associations between the gut microbiota and cancer. Their potential for noninvasive cancer screening is explored systematically.

Smoking‐associated epigenetic changes have been linked to lung cancer (LC) risk; however, the role of epigenetic alterations independent of smoking is yet to be fully understood. This study aimed to validate 16 previously reported CpG sites that are independent of smoking yet associated with LC risk within a population‐based prospective cohort. Using the Infinium Methylation EPIC BeadChip kit or the Infinium HumanMethylation450K BeadChip Assay, DNA methylation (DNAm) in whole blood was assessed in four subsets (n = 736, 1027, 997, and 312) of a population‐based cohort from Germany. The DNAm levels of the 16 smoking‐independent CpG sites were analyzed. Hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated to assess associations of DNAm at the 16 CpG sites with LC risk, adjusting for multiple covariates, including smoking habits and a smoking‐associated DNAm score. Over 17 years of follow‐up, a total of 199 LCs were observed. Among the 16 CpGs, cg02211449 showed a negative association with LC risk (HR [95% CI] per SD increase, = 0.70 [0.63–0.78]), while cg11385536 (1.04 [1.01–1.07]), cg09736286 (1.64 [1.10–2.44]), cg19907023 (1.64 [1.01–2.66]), and cg22032485 (1.52 [1.04–2.21]) displayed positive associations with LC risk. Five of the 16 suggested smoking‐independent CpGs could be externally validated as predictors of LC risk. Further research should address their potential contribution to enhanced LC risk stratification. This study validated 16 CpG sites independent of smoking and their association with lung cancer (LC) risk in a population‐based cohort from Germany. Among these, five CpGs were significantly associated with LC risk, suggesting their potential utility in enhancing LC risk prediction beyond smoking‐related factors.

We recently derived and validated a serum‐based microRNA risk score (miR‐score) that predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow‐up in a population‐based cohort study from Germany (ESTHER cohort). Here, we aimed to evaluate associations of the CRC‐specific miR‐score with the risk of developing other common cancers, including female breast cancer (BC), lung cancer (LC), and prostate cancer (PC), in the ESTHER cohort. MicroRNAs (miRNAs) were profiled by quantitative real‐time PCR in serum samples collected at baseline from randomly selected incident cases of BC (n = 90), LC (n = 88), and PC (n = 93) and participants without diagnosis of CRC, LC, BC, or PC (controls, n = 181) until the end of the 17‐year follow‐up. Multivariate logistic regression models were used to evaluate the associations of the miR‐score with BC, LC, and PC incidence. The miR‐score showed strong inverse associations with BC and LC incidence [odds ratio per 1 standard deviation increase: 0.60 (95% confidence interval [CI] 0.43–0.82), p = 0.0017, and 0.64 (95% CI 0.48–0.84),p = 0.0015, respectively]. Associations with PC were not statistically significant but pointed in the positive direction. Our study highlights the potential of serum‐based miRNA biomarkers for cancer‐specific risk prediction. Further large cohort studies aiming to investigate, validate, and optimize the use of circulating miRNA signatures for cancer risk assessment are warranted. Circulating microRNAs (miRNAs) could improve cancer risk prediction. Our findings demonstrate that miRNA profiles associated with tumor progression differ across cancer types and could be useful for developing personalized cancer prevention strategies.

Blood‐based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two‐stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age‐ and gender‐matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early‐ or late‐stage CRC was derived by least absolute shrinkage and selection operator regression with .632+ bootstrap method, and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n = 56 and 102, respectively). Three different signatures for all‐, early‐, and late‐stage CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.92, 0.91, and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 [95% confidence interval (95% CI), 0.67–0.84], 0.75 (95% CI, 0.62–0.87), and 0.80 (95% CI, 0.68–0.89) for all‐, early‐, and late‐stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood‐based tests for CRC early detection in the future. A signature consisting of 12 plasma protein biomarkers derived in a clinical setting and independently validated in a true screening setting (participants of screening colonoscopy) yielded area under the curves of 0.91 and 0.75 for distinguishing early‐stage colorectal cases from controls free of neoplasms. These 12 protein markers may contribute to the development of blood‐based tests for population‐based screening.

Bovine milk and meat factors (BMMFs) are plasmid‐like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co‐markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor‐adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low‐/high‐grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co‐immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor‐adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD‐adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC‐specific death were increased for higher Rep expression (TMA), with high tumor‐adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF‐specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC. BMMFs are a group of infectious agents related to indirect carcinogenesis. Macrophage expression of the conserved BMMF Rep protein in tumor‐adjacent mucosa of CRC patients is increased compared with expression in the tumor and mucosa of healthy donors, indicating that BMMF is involved in inflammation‐driven, indirect carcinogenesis of CRC (zur Hausen 2009). Even after resection and therapy, Rep expression persists and might favor ongoing chronic inflammation, tumor recurrence and metastasis. Rep might, therefore, serve as prognostic marker for CRC.

Introduction Sleep problems are common among cancer patients. The relationship between sleep disruption and clinical outcomes after colorectal cancer (CRC) diagnosis remains poorly understood. We investigated associations of sleep disruption with survival and recurrence in patients with CRC. Methods CRC patients with stages I–IV (N = 895) were included in this study. Self‐reported sleep disturbance was assessed presurgery using the sleep item from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core‐30 and classified into “no/mild” or “moderate/severe” sleep disturbance. Cox‐proportional hazard models were computed (HRs and 95% confidence intervals) to investigate associations of sleep disturbance with overall survival (OS), disease‐free survival (DFS), and risk of recurrence, adjusting for age, sex, body mass index, tumor stage and site, and study site. Results Thirty percent of patients reported moderate/severe sleep disturbance. N = 190 (21%) were deceased after a median follow‐up of 31 months, whereas 74 patients (15%) had a recurrence. Patients with moderate/severe vs. no/mild sleep disturbance had worse OS (HR = 1.46; 95% CI = 1.07–1.98; p = 0.02). There were no significant associations for sleep disturbance with DFS and risk of recurrence. Stratified analyses indicated that the worse OS rates due to sleep disturbance were stronger in patients who were middle‐aged and older, male, overweight/obese, diagnosed with rectal cancer and stage I–III. Conclusions Poor sleep is common among CRC patients and is associated with worse overall survival. These findings highlight the potential value of preoperative sleep screening as a way to identify patients at higher risk of poor outcomes, warranting further investigation in future studies. Trial Registration ClinicalTrials.gov identifier: NCT02328677

Background We previously observed decreasing resection rates of non‐metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non‐metastatic GaC at the population level remain unclear. This large international population‐based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable‐adjusted trends in the long‐term OS of patients with non‐metastatic GaC. Methods Individual‐level data of patients with non‐metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. Results A total of 66,398 non‐metastatic GaC patients diagnosed in 2003‐2016 were analyzed, with an accumulated follow‐up of 172,357 person‐years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR)per year = 0.99; HR≥ vs. <2010 = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HRper year = 1.03; HR≥ vs. <2010 = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HRper year = 0.98; HR≥ vs. <2010 = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HRper year = 0.99; HR≥ vs. <2010 = 0.92) and Norway (HRper year = 0.97; HR≥ vs. <2010 = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non‐metastatic GaCs regarding the associations between year of diagnosis and survival. Conclusions OS of patients with non‐metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21st century. Progress in OS of patients with non‐metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality globally. Fecal miRNAs have been suggested to be promising biomarkers for CRC early detection. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. PubMed and Web of Science were searched to retrieve relevant articles published up to 7 December 2021. Information on study design, characteristics of study population, pre-analytics (sample collection, processing, and storage), fecal miRNA extraction and quantification technologies, and diagnostic performance (including sensitivity, specificity, and area under the curve (AUC)) were summarized. Twenty studies reporting on 31 individual miRNAs and 16 miRNA panels (with 2–9 markers) for CRC diagnosis were identified. Substantial heterogeneity existed regarding stool sample collection, processing, storage, and miRNA extraction and normalization. For two individual miRNAs and one miRNA panel, values ≥ 80% were reported for both sensitivity and specificity; however, none of these results were either internally or externally validated. In a study among fecal immunochemical test-positive cases recruited from a true screening setting, better diagnostic performance was identified and internally validated for a combination panel including two miRNAs, fecal hemoglobin level, and patient age and sex, compared with fecal hemoglobin concentration alone. Fecal miRNAs or miRNA panels, possibly in combination with fecal hemoglobin test, may be promising candidates for noninvasive CRC early detection. However, large prospective and well-designed studies in CRC screening cohorts are required to validate promising miRNAs or miRNA panels.

Circulating microRNAs (miRNAs) could improve colorectal cancer (CRC) risk prediction. Here, we derive a blood-based miRNA panel and evaluate its ability to predict CRC occurrence in a population-based cohort of adults aged 50–75 years. Forty-one miRNAs are preselected from independent studies and measured by quantitative-real-time-polymerase-chain-reaction in serum collected at baseline of 198 participants who develop CRC during 14 years of follow-up and 178 randomly selected controls. A 7-miRNA score is derived by logistic regression. Its predictive ability, quantified by the optimism-corrected area-under-the-receiver-operating-characteristic-curve (AUC) using .632+ bootstrap is 0.794. Predictive ability is compared to that of an environmental risk score (ERS) based on known risk factors and a polygenic risk score (PRS) based on 140 previously identified single-nucleotide-polymorphisms. In participants with all scores available, optimism-corrected-AUC is 0.802 for the 7-miRNA score, while AUC (95% CI) is 0.557 (0.498–0.616) for the ERS and 0.622 (0.564–0.681) for the PRS. Appropriate risk models could facilitate risk stratification for colorectal cancer (CRC) screening. Here, the authors propose a blood-based microRNA signature observed to have altered expression in pre-diagnostic samples, which might be useful to identify high-risk populations for colorectal cancer screening.