Apc-mutant cells act as supercompetitors in intestinal tumour initiation.

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3ß. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death.

BACKGROUND: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. METHODS: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio either to receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. RESULTS: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). CONCLUSIONS: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

Risk of Cancers Proximal to the Colon in Fecal Immunochemical Test Positive Screenees in a Colorectal Cancer Screening Program.

BACKGROUND & AIMS: In more than half of the colorectal cancer screening participants with a positive fecal immunochemical test (FIT) result, no advanced neoplasia (AN) is detected at colonoscopy. The positive FIT result could also be generated by cancers located proximal to the colon: upper gastrointestinal, oral cavity, nose, and throat cancers. We evaluated screenees' risk of being diagnosed with a cancer proximal to the colon within the 3 years and compared risks between those with a positive vs those with a negative FIT. METHODS: Data of Dutch colorectal cancer screening participants who underwent biennial FIT-based screening 2014-2018 were collected from the national screening database and linked to the National Cancer Registry. Screenees were classified into 3 groups: FIT-positives with AN (FIT+/AN+), FIT-positives without AN (FIT+/AN-), and FIT-negatives (FIT-). We compared the cumulative incidence of cancers proximal to the colon in each group 3 years after FIT. A Cox regression analysis with left truncation and right censoring, using FIT positivity as time-dependent variable and stratified for sex, was performed to compare the hazard of cancers proximal to the colon in participants who were FIT-positive vs FIT-negative. RESULTS: Three-year cumulative incidence of cancers proximal to the colon in FIT+/AN+ (n = 65,767), FIT+/AN- (n = 50,661), and FIT- (n = 1,831,647) screenees was 0.7%, 0.6%, and 0.4%, respectively (P < .001). FIT-positives were older and more frequently male than FIT-negatives (P < .001). Significantly more cancers proximal to the colon were detected among FIT-positives (P < .001; hazard ratio, 1.55; 95% CI, 1.44-1.67). CONCLUSION: FIT-positive screenees were at significantly increased risk of being diagnosed with a cancer proximal to the colon within 3 years after FIT, although the 3-year cumulative incidence was still less than 1%.

Combining Colonoscopy With Fecal Immunochemical Test Can Improve Current Familial Colorectal Cancer Colonoscopy Surveillance: A Modelling Study.

BACKGROUND & AIMS: The authors assessed whether familial colorectal cancer (FCRC) surveillance in individuals without hereditary CRC can be optimized METHODS: The Adenoma and Serrated Pathway to Colorectal Cancer-FCRC model simulates CRC development in individuals with a family history of CRC at 2-fold and 4-fold increased CRC risk compared with the general population. The authors simulated a strategy without surveillance, the current Dutch guideline (5-yearly colonoscopy between ages 45 and 75 years), and the following 3 sets of alternative strategies: colonoscopy surveillance, surveillance combining colonoscopy and fecal immunochemical test (FIT), and FIT-based surveillance. Each set included a range of strategies differing in age range and test interval. The optimal strategy was defined as the strategy with highest quality-adjusted life-years (QALYs) satisfying all of the following criteria: in the (near-)efficiency area of the cost-effectiveness frontier and compared with current surveillance; noninferior effectiveness; no substantial increase in colonoscopy burden; and not more expensive. RESULTS: The optimal strategy was 10-yearly colonoscopy with 2-yearly FIT between colonoscopies from ages 40 to 80 years for both 2-fold and 4-fold increased CRC risk. At 2-fold risk, this strategy prevented 0.8 more CRC deaths, gained 15.8 more QALYs at 731 fewer colonoscopies, and saved €98,000 over the lifetime of 1000 individuals compared with current surveillance. At 4-fold risk, figures were 2.1 more CRC deaths prevented, 37.0 more QALYs gained at 567 fewer colonoscopies, and €127,000 lower costs. Current surveillance was not (near-)efficient. CONCLUSIONS: FIT could play an important role in FCRC surveillance. Surveillance with 10-yearly colonoscopy and 2-yearly FIT between colonoscopies from ages 40 to 80 years increased QALYs and reduced colonoscopy burden and costs compared with current FCRC surveillance.

Stool-Based Testing for Post-Polypectomy Colorectal Cancer Surveillance Safely Reduces Colonoscopies: The Molecular Stool Testing for Colorectal Cancer Surveillance Study.

BACKGROUND & AIMS: Colonoscopy-based surveillance to prevent colorectal cancer (CRC) causes substantial burden for patients and health care. Stool tests may help to reduce surveillance colonoscopies by limiting colonoscopies to individuals at increased risk of advanced neoplasia. METHODS: This cross-sectional observational study included individuals aged 50-75 years with surveillance indication. Before bowel preparation, participants collected samples for a multitarget stool DNA test and 2 fecal immunochemical tests (FITs). Test accuracy was calculated for all surveillance indications. For the post-polypectomy indication only, which is the most common and is associated with a relatively low CRC risk, long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer model. Stool-based strategies were simulated to tune each test's positivity threshold to obtain strategies at least as effective as colonoscopy surveillance. RESULTS: There were 3453 individuals with results for all stool tests and colonoscopy; 2226 had previous polypectomy, 1003 had previous CRC, and 224 had a familial risk. Areas under the receiver operating characteristic curve for advanced neoplasia were 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test, 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR (Eiken Chemical Co, Tokyo, Japan) and 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold (Sentinel, Milan, Italy). Stool-based post-polypectomy surveillance strategies at least as effective as colonoscopy surveillance reduced the number of colonoscopies by 15%-41% and required 5.6-9.5 stool tests over a person's lifetime. Multitarget stool DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs. CONCLUSIONS: This study found that stool-based post-polypectomy surveillance strategies can be safe and cost-effective, with potential to reduce the number of colonoscopies by up to 41%. CLINICALTRIALS: gov, Number: NCT02715141.

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Computer-Aided Diagnosis for Leaving Colorectal Polyps In Situ : A Systematic Review and Meta-analysis.

BACKGROUND: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. PURPOSE: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. DATA SOURCES: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. STUDY SELECTION: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. DATA EXTRACTION: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. DATA SYNTHESIS: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). LIMITATION: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. CONCLUSION: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. PRIMARY FUNDING SOURCE: European Commission. (PROSPERO: CRD42023402197).

The multitarget faecal immunochemical test for improving stool-based colorectal cancer screening programmes: a Dutch population-based, paired-design, intervention study.

BACKGROUND: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening. METHODS: Individuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 µg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete. FINDINGS: Between March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening. INTERPRETATION: The higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening. FUNDING: Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.

Current Approaches in Managing Colonic Serrated Polyps and Serrated Polyposis.

For decades, conventional adenomas were the only known precursor lesions of colorectal cancer (CRC). Accordingly, education and research regarding CRC prevention were mainly focused on adenomas. The groundbreaking discovery that serrated polyps (SPs) also have the potential to develop into CRCs, and seem to account for a considerable proportion of sporadic CRCs, has led to a paradigm shift in the prevention, diagnosis, and treatment of CRC. Studies in recent years have led to our current understanding of SPs and associated CRC, but a lot of work is still to be done to further improve knowledge about this serrated neoplasia pathway and the clinical management of SPs and serrated polyposis syndrome (SPS). In this review, we reflect on the current understanding of SPs with respect to terminology, detection, resection, and surveillance and reflect on the management of SPS.

Accuracy of Computer-aided Diagnosis in Colonoscopy Varies According to Polyp Location: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Computer-aided diagnosis (CADx) assists endoscopists in differentiating between neoplastic and non-neoplastic polyps during colonoscopy. This study aimed to evaluate the impact of polyp location (proximal vs. distal colon) on the diagnostic performance of CADx for ≤5 mm polyps. METHODS: We searched for studies evaluating the performance of real-time CADx alone (ie, independently of endoscopist judgement) for predicting the histology of colorectal polyps ≤5 mm. The primary endpoints were CADx sensitivity and specificity in the proximal and distal colon. Secondary outcomes were the negative predictive value (NPV), positive predictive value (PPV), and the accuracy of the CADx alone. Distal colon was limited to the rectum and sigmoid. RESULTS: We included 11 studies for analysis with a total of 7782 polyps ≤5 mm. CADx specificity was significantly lower in the proximal colon compared with the distal colon (62% vs 85%; risk ratio (RR), 0.74; 95% confidence interval [CI], 0.72-0.84). Conversely, sensitivity was similar (89% vs 87%); RR, 1.00; 95% CI, 0.97-1.03). The NPV (64% vs 93%; RR, 0.71; 95% CI, 0.64-0.79) and accuracy (81% vs 86%; RR, 0.95; 95% CI, 0.91-0.99) were significantly lower in the proximal than distal colon, whereas PPV was higher in the proximal colon (87% vs 76%; RR, 1.11; 95% CI, 1.06-1.17). CONCLUSION: The diagnostic performance of CADx for polyps in the proximal colon is inadequate, exhibiting significantly lower specificity compared with its performance for distal polyps. Although current CADx systems are suitable for use in the distal colon, they should not be employed for proximal polyps until more performant systems are developed specifically for these lesions.