BRAF mutated colorectal cancer (CRC) often demonstrates distinct molecular profiles characterized by a high methylator phenotype with two different microsatellite statuses (MSI and MSS) and corresponding methylation spectra. Prognostic disparities between these two different BRAF mutated CRC arise from divergent carcinogenic pathways, with BRAF-mutated MSS CRC exhibiting particularly unfavorable clinical outcomes. The underlying mechanism of these phenomena stems from epigenetic heterogeneity in methylation landscapes. Emerging evidences linking cholelithiasis and deoxycholic acid (DCA) to BRAF-mutated CRC pathogenesis warrant systematic investigation into their potential mechanistic relationships. Elucidating these connections could unravel novel pathogenetic pathways and inform targeted strategies for risk mitigation, molecular diagnostics, and therapeutic intervention of BRAF-mutated CRC.

Serrated polyps can progress to colorectal cancer (CRC), through a pathway that is distinct from the conventional adenoma-carcinoma sequence. This pathway includes hyperplastic polyps (HPs), sessile serrated polyps (SSPs), and traditional serrated adenomas (TSAs).

Our review includes the histology and pathological challenges, carcinogenesis, risk factors, detection, emerging technologies, resection, and surveillance.

Serrated polyp management presents many detection, diagnosis, resection, and surveillance challenges. Missed serrated polyps contribute to preventable CRCs. A new SSP detection rate benchmark will guide endoscopists with a goal when improving detection. Furthermore, new SSP-specific surveillance strategies may also aid in reducing CRC burden. Histologic differentiation remains a challenge, underscoring the need for standardized pathology practices and exploring novel ways to stratify risk independent of histology, given interobserver variation. Moreover, the clinical significance of proximal HPs requires further clarification. Which HPs < 1 cm require closer surveillance intervals? Molecular profiling may help identify markers that separate proximal low risk from high-risk HP. The best approach for resection of serrated polyps also needs to be clarified. There is also a lack of robust longitudinal outcome data to guide surveillance recommendations since current guidelines are based on low quality of evidence.

Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.

ObjectiveThis study aimed to explore the risk factors for colorectal sessile serrated lesions and construct a risk nomogram model.MethodsPatients were enrolled retrospectively from the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University from January 2019 to September 2023 and randomized to the training and validation sets at a ratio of 7:3. The predictors for constructing the nomogram model were screened via univariate analysis and multivariate logistic regression analysis. Subsequently, the performance of the model was evaluated.ResultsMultivariate logistic regression analysis revealed that age, history of smoking, history of alcohol consumption, and triglyceride-glucose index were independent risk factors for colorectal sessile serrated lesions (p < 0.05). The area under the curve values of the nomogram model in the training and validation sets were 0.715 (95% confidence interval: 0.676-0.753) and 0.742 (95% confidence interval: 0.669-0.815), respectively. The calibration curves showed good homogeneity between the predicted and actual values. Decision curve analysis showed that this nomogram model can achieve positive clinical benefits.ConclusionsAge, history of smoking, history of alcohol consumption, and triglyceride-glucose index are independent predictors of colorectal sessile serrated lesions. This nomogram model may predict the risk of colorectal sessile serrated lesions.

Polyps located in less accessible areas of the colon, such as inner curves of flexures, are often difficult to visualize. Colonoscope attachments such as the Endocuff have been developed to improve the visualization of these polyps. We aimed to assess the utility of Endocuff-assisted colonoscopy (EAC) in the detection of tubular adenomas and sessile serrated polyps (SSP) compared to conventional colonoscopy during routine colorectal cancer screening.

This retrospective cohort study included patients who underwent colorectal cancer screening with either conventional colonoscopy or EAC between November 2022 and March 2023. The primary outcomes were SSP and tubular adenoma detection rates. Secondary outcomes included total procedure time, cecal intubation time, and ileal intubation rates.

Of the 435 patients included, 189 (43%) underwent EAC, and 246 (57%) underwent conventional colonoscopy. The mean ± standard deviation number of polyps detected was 1.7 ± 2.2, the mean procedure time was 18.7 ± 7.5 min, and the mean cecal intubation time was 4.4 ± 3.3 min, with no significant differences between groups. A smaller proportion of patients in the EAC group had successful ileal intubation (14% vs. 55%; p < 0.01). The tubular adenoma detection rate was similar between EAC and conventional colonoscopy (41% vs. 39%; p = 0.70), but the SSP detection rate was significantly higher with EAC (16% vs. 8.5%; p < 0.01).

EAC may enhance the detection of difficult-to-visualize SSPs during screening colonoscopies without affecting overall procedure time. However, physicians should consider the examination indication when selecting EAC, as ileal intubation may be more challenging.

Sessile serrated lesions (SSL) and conventional serrated adenomas (TSA) are precursors to colon cancer. This study explores the potential use of medical thermal imaging to detect CYFRA 21-1 and neuronal specific enolase (NSE) in the identification and monitoring of sessile serrated lesions and conventional serrated adenomas. To evaluate the association between serum levels of CYFRA 21-1 and NSE with sessile serrated lesions and conventional serrated adenomas, and to explore the validity of a diagnostic scoring system based on thermal imaging. In this study, clinical data and relevant laboratory indicators, including serum levels of CYFRA 21-1 and NSE, were collected from eligible patients. Statistical analysis was used to assess the association of these tumor markers with the risk of SSL/TSA, and a diagnostic scoring system was developed to improve the identification accuracy. The study showed that levels of CYFRA 21-1 and NSE were significantly associated with SSL/TSA risk. Through data analysis, the diagnostic scoring system developed can effectively improve the accuracy of SSL/TSA recognition. The auxiliary analysis showed that medical thermal imaging technology provides additional value in monitoring lesions, and combined with medical thermal imaging technology can significantly improve the accuracy of diagnosis and provide new strategies for the early prevention of colon cancer.

Sessile serrated lesions (SSLs) are recognized as precursor lesions in the pathogenesis of colorectal cancer, particularly in the context of microsatellite instability (MSI). This study evaluates the role of immunohistochemical (IHC) markers in understanding the molecular and immunologic characteristics of SSLs.

A retrospective analysis was performed on 45 colonic neoplastic lesions diagnosed as SSLs. An IHC staining panel was conducted, including MLH1, p53, CD44, CD3, CD8, MUC2, MUC5AC, MUC6, chromogranin and Ki67 antibodies.

MLH1 and p53 expressions showed correlations with dysplastic changes. Immunological markers CD3 and CD8 indicated a variable immune response, potentially reflecting the tumor's ability to evade immune surveillance in certain situations. CD44 was overexpressed in all SSLs. The number of neuroendocrine cells was overall reduced.

SSLs are heterogeneous lesions, exhibiting a wide range of histological and molecular features. Using IHC might enhance diagnostic accuracy, particularly in lesions with ambiguous histological features, when dysplasia develops. Accurate identification of SSLs and understanding their molecular characteristics are crucial for assessing their malignant potential.

White light (conventional) colonoscopy (WLC) is widely used for colorectal cancer screening, diagnosis and surveillance but endoscopists may fail to detect adenomas. Our goal was to assess and synthesize overall and subgroup-specific adenoma miss rates (AMR) of WLC in daily practice.

We conducted a systematic review in MEDLINE, EMBASE, Cochrane Library, and grey literature on studies evaluating diagnostic WLC accuracy in tandem studies with novel-colonoscopic technologies (NCT) in subjects undergoing screening, diagnostic or surveillance colonoscopy. Information on study design, AMR overall and specific for adenoma size, histology, location, morphology and further outcomes were extracted and reported in standardized evidence tables. Study quality was assessed using the QUADAS-2 tool. Random-effects meta-analyses and meta-regression were performed to estimate pooled estimates for AMR with 95% confidence intervals (95% CI) and to explain heterogeneity.

Out of 5,963 identified studies, we included sixteen studies with 4,101 individuals in our meta-analysis. One in three adenomas (34%; 95% CI: 30-38%) was missed by WLC in daily practice individuals. Subgroup analyses showed significant AMR differences by size (36%, adenomas 1-5 mm; 27%, adenomas 6-9 mm; 12%, adenomas ≥ 10 mm), histology (non-advanced: 42%, advanced: 21%), morphology (flat: 50%, polypoid: 27%), but not by location (distal: 36%, proximal: 36%).

Based on our meta-analysis, one in three adenomas could be missed by WLC. This may significantly contribute to interval cancers. Our results should be considered in health technology assessment when interpreting sensitivity of fecal occult blood or other screening tests derived from studies using WLC as "gold standard".

Oxidative stress has been implicated as a pivotal factor in the pathogenesis of numerous malignancies. However, the association between oxidative stress and the prognosis of patients with colorectal cancer liver metastasis (CRCLM) is not well elucidated. We conducted a retrospective analysis of 424 patients with CRCLM who underwent primary resection at the Union Hospital, Tongji Medical College, Wuhan, between July 2013 and September 2018. Patients were randomly divided into a training set (n = 300) and a test set (n = 124) in a 7:3 ratio.To develop the CRCLM-integrated Oxidative Stress Score (CLIOSS) for CRCLM, we utilized individual oxidative stress markers. The overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and the log-rank test was employed to assess prognostic factors.To validate the predictive performance of CLIOSS, we constructed Receiver Operating Characteristic (ROC) curves and calculated the Area Under the Curve (AUC) values. Additionally, Decision Curve Analysis (DCA) and calibration plots were used to evaluate the clinical utility and predictive consistency of the model. The CLIOSS prognostic model was constructed based on the following variables and their corresponding β coefficients: 0.042 × total bilirubin (TBIL, µmol/L) + 0.032 × blood urea nitrogen (BUN, mmol/L) - 0.001 × uric acid (UA, µmol/L). Higher CLIOSS were associated with poorer OS (2.934;95% CI 2.167-3.974;P < 0.001) and DFS(2.707; 95% CI 2.000-3.664; P  < 0.001. The 3-year OS AUC values were 0.803 in the training set and 0.851 in the testset, while the 3-year DFS AUC values were 0.892 and 0.898, respectively. Decision curve analysis demonstrated that both predictive models have significant clinical utility in practice. CLIOSS is a comprehensive prognostic index derived from oxidative stress markers, designed to predict long-term survival in patients with CRCLM. Our study shows that higher CLIOSS are significantly associated with poorer outcomes, making it an important tool for assessing patient risk.

Many patients with colorectal polyposis demonstrate negative results in germline mutation test. This study aimed to uncover genetic variants associated with nonhereditary colorectal polyposis using a genome-wide association study (GWAS).

At a single referral university hospital, between January 2012 and September 2021, 638 patients with ≥ 10 biopsy-proven cumulative polyps on colonoscopy without germline mutations related to hereditary colorectal cancer or polyposis were included. The control group comprised 1863 individuals from the Korea Medical Institute, each having undergone at least two colonoscopies, all of which were normal. This study utilized GWAS to identify susceptibility loci for nonhereditary colorectal polyposis. Genetic differences between patients with and without ≥ 10 polyp recurrences were analyzed using Cox proportional hazards models.

GWAS revealed 71 novel risk single-nucleotide polymorphisms (SNPs) not seen in previous colorectal cancer and polyp GWAS. Five genes (UPF3A, BICRA, CBWD6, PDE4DIP, and ABCC4) overlapping seven SNPs (rs566295755, rs2770288, rs1012003, rs201270202, rs71264659, rs1699813, and rs149368557), previously linked to colorectal cancer, were identified as significant risk factors for nonhereditary colorectal polyposis. Two novel genes (CNTN4 and CNTNAP3B), not previously associated with colorectal diseases, were identified. Three SNPs (rs149368557, rs12438834, and rs9707935) were significantly associated with higher risk of recurrence of polyposis. The gene overlapping with rs149368557 was ABCC4, which was also significantly associated with an increased risk of nonhereditary colorectal polyposis.

This study identified 71 novel risk variants for nonhereditary colorectal polyposis, with three SNPs (rs149368557, rs12438834, and rs9707935) indicating significant associations with increased risk of polyposis recurrence.

Colorectal cancer (CRC) is a common cancer, with a concerning rise in early-onset CRC cases, signalling a shift in disease epidemiology. Whilst our understanding of the molecular underpinnings of CRC has expanded, the complexities underlying its initiation remain elusive, with emerging evidence implicating the microbiome in CRC pathogenesis. This review synthesizes current knowledge on the intricate interplay between the microbiome, tumour microenvironment (TME), and molecular pathways driving CRC carcinogenesis. Recent studies have reported how the microbiome may modulate the TME and tumour immune responses, consequently influencing cancer progression, and whilst specific bacteria have been linked with CRC, the underlying mechanisms remains poorly understood. By elucidating the functional links between microbial landscapes and carcinogenesis pathways, this review offers insights into how bacteria orchestrate diverse pathways of CRC development, shedding light on potential therapeutic targets and personalized intervention strategies.

We present the case of a 68-year-old woman who underwent complete endoscopic resection of a superficial serrated adenoma (SuSA). Due to its rarity and limited case reports, SuSA is often misdiagnosed as a hyperplastic lesion without malignant potential, leading to missed diagnoses. A polypoid lesion was identified in the sigmoid colon during the initial endoscopic evaluation, where it was initially classified as a sessile serrated lesion (SSL). The subsequent endoscopic evaluation, using crystal violet staining, revealed a type IIIL pit pattern. Endoscopic mucosal resection (EMR) was performed, and histopathological analysis confirmed serrated glandular hyperplasia with mild atypia. Immunohistochemical staining showed cytokeratin 20 (CK20) expression predominantly in the upper layer, while Ki-67 and cellular myelocytomatosis oncogene (c-MYC) were distributed in the basal and intermediate layers. Beta-catenin positivity was observed in the cytoplasm of some nuclei, confirming the diagnosis of SuSA. This case underscores the importance of timely recognition and management of SuSA to prevent progression to more severe conditions.

Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal cancer exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive mutations in wild-type human gut organoids. Here, we demonstrate that long-term culture of mismatch-repair-deficient organoids allows the selection of spontaneous oncogenic mutations through the sequential withdrawal of Wnt agonists, epidermal growth factor (EGF) agonists and the bone morphogenetic protein (BMP) antagonist Noggin, while TP53 mutations were selected through the addition of Nutlin-3. Thus, organoids sequentially acquired mutations in AXIN1 and AXIN2 (Wnt pathway), TP53, ACVR2A and BMPR2 (BMP pathway) and NRAS (EGF pathway), gaining complete independence from stem cell niche factors. Quadruple-pathway (Wnt, EGF receptor, p53 and BMP) mutant organoids formed solid tumors upon xenotransplantation. This demonstrates that carcinogenesis can be recapitulated in a DNA repair-mutant background through in vitro selection that targets four consecutive cancer pathways.

The potential of molecular markers in the removed polys as reliable predictors of metachronous lesions is still uncertain.

Our aim was to evaluate the role of somatic mutations in KRAS in polyps of patients with high-risk adenomas to predict the risk of advanced polyps or colorectal cancer (CRC) within 3 years.

A total of 518 patients were prospectively enrolled. The included patients had adenomas ≥10 mm, high-grade dysplasia, villous component or ≥3 more adenomas at baseline and were scheduled to undergo surveillance colonoscopy at 3 years ± 6 months. Somatic KRAS mutation was performed on 1189 polyps collected from these patients. At surveillance, advanced lesions were defined as adenomas with a size of ≥10 mm. High-grade dysplasia or villous component, serrated polyps ≥10 mm or with dysplasia or CRC.

At baseline, 81 patients (15.6%) had KRAS mutations in at least one polyp. Patients with KRAS mutated polyps had more frequent villous histological lesions and size ≥20 mm. In the multivariate analysis, adjusted for age and sex, only age (odds ratios [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; p < 0.001), ≥5 adenomas (OR, 3.92; 95% CI, 1.96-7.82), and KRAS mutation (OR, 2.54; 95% CI, 1.48-4.34; p < 0.01) were independently associated with the development of advanced lesions at surveillance.

Our results show that, in patients with high-risk adenomas, the presence of somatic mutations in KRAS is an independent risk factor for the development of advanced metachronous polyps.

Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.

Serrated lesions are common precancerous pathways in colorectal cancer (CRC), but the process by which they progress to malignancy remains unclear. We aimed to elucidate this progression through a single-cell RNA landscape. We conducted single-cell RNA sequencing on three normal colonic tissues and fifteen SLs (including HPs, SSLs, SSLD, and TSAs) and integrated these data with datasets containing tumor samples. We identified three invasive malignant epithelial cell subtypes related to CRC progression: SLC1, SLC2, and tumor cell. SLC1, specific to SSLs, is involved in cell proliferation and shows a continuum of malignancy in gene expression. TSA-specific SLC2 exhibited FOXQ1 upregulation and active EMT, indicating invasiveness. The trajectory analysis showed that HPs do not progress to cancer, and different SL types are linked to the MSI status of advanced CRCs. We validated molecular drivers in premalignant lesions and later carcinogenesis. In the tumor microenvironment, CAF and pre-CAF fibroblast subtypes associated with progression were identified. During the premalignant stage, SLC1 triggered CD8+ T cell responses, while at the advanced stage, CAFs promoted tumor invasion and metastasis via FN1-CD44, influencing tumor progression and the treatment response. Our findings highlight transcriptional changes across serrated pathway stages, aiding in early CRC diagnosis and treatment.

Tumor progression is driven by the accumulation of genetic alterations, including both point mutations and copy number changes. Understanding the temporal sequence of these events is crucial for comprehending the disease but is not directly discernible from cross-sectional genomic data. Cancer progression models, including Mutual Hazard Networks (MHNs), aim to reconstruct the dynamics of tumor progression by learning the causal interactions between genetic events based on their co-occurrence patterns in cross-sectional data. Here, we highlight a commonly overlooked bias in cross-sectional datasets that can distort progression modeling. Tumors become clinically detectable when they cause symptoms or are identified through imaging or tests. Detection factors, such as size, inflammation (fever, fatigue), and elevated biochemical markers, are influenced by genomic alterations. Ignoring these effects leads to "conditioning on a collider" bias, where events making the tumor more observable appear anticorrelated, creating false suppressive effects or masking promoting effects among genetic events. We enhance MHNs by incorporating the effects of genetic progression events on the inclusion of a tumor in a dataset, thus correcting for collider bias. We derive an efficient tensor formula for the likelihood function and apply it to two datasets from the MSK-IMPACT study. In colon adenocarcinoma, we observe a significantly higher rate of clinical detection for TP53-positive tumors, while in lung adenocarcinoma, the same is true for EGFR-positive tumors. Compared to classical MHNs, this approach eliminates several spurious suppressive interactions and uncovers multiple promoting effects.

There are several types of colorectal cancer (CRC) according to the detection methods and intervals, including interval CRC (iCRC) and postcolonoscopy CRC (PCCRC). We aimed to examine their proportions and characteristics.

We conducted a multicenter prospective study using questionnaires in Japan ("C-DETECT study"), in which differences in CRC characteristics according to detection methods and intervals were examined from consecutive adult patients. Because the annual fecal immunochemical test (FIT) was used in population-based screening, the annual FIT-iCRC was assessed.

In total, 1241 CRC patients (1064 with invasive CRC) were included. Annual FIT-iCRC (a), 3-year PCCRC (b), and CRC detected within 1 year after a positive FIT with noncompliance to colonoscopy (c) accounted for 4.5%, 7.0%, and 3.9% of all CRCs, respectively, and for 3.9%, 5.4%, and 4.3% of invasive CRCs, respectively. The comparison among these (a, b, c) and other CRCs (d) demonstrated differences in the proportions of ≥T2 invasion ([a] 58.9%, [b] 44.8%, [c] 87.5%, [d] 73.0%), metastasis ([a] 33.9%, [b] 21.8%, [c] 54.2%, [d] 43.9%), right-sided CRC ([a] 42.9%, [b] 40.2%, [c] 18.8%, [d] 28.6%), and female sex ([a] 53.6%, [b] 49.4%, [c] 27.1%, [d] 41.6%). In metastatic CRC, (a) and (b) showed a higher proportions of BRAF mutations ([a] [b] 12.0%, [c] [d] 3.1%).

Annual FIT-iCRC and 3-year PCCRC existed in nonnegligible proportions. They were characterized by higher proportions of right-sided tumors, female sex, and BRAF mutations. These findings suggest that annual FIT-iCRC and 3-year PCCRC may have biological features different from those of other CRCs.

Serrated polyps (SPs) are precursors to 15% to 20% of colorectal cancers (CRCs). However, there are uncertainties regarding which SPs require surveillance and at what intervals, with recommendations adapted from those for adenomas in the absence of solid evidence. Our aim was to assess which SP risk characteristics relate to a higher risk of metachronous CRC or advanced polyps.

We systematically searched PubMed, Embase, and Cochrane for cohort studies, case-control studies, and clinical trials from inception to December 31, 2023, of CRC or advanced polyps (advanced adenoma [AA] or advanced SP) incidence at surveillance stratified by baseline SP size, dysplasia, location, and multiplicity. We defined advanced SPs as those ≥10 mm or with dysplasia. CRC and advanced polyp incidence per 1000 person-years were estimated. We performed a meta-analysis by calculating pooled relative risks (RRs) using a random-effects model.

A total of 5903 studies were reviewed, and 14 were included with 493,949 patients (mean age, 59.5 years; 55% men). The mean follow-up was 4.9 years. CRC incidence per 1000 person-years was 2.09 (95% confidence interval [CI], 1.29-2.90) for advanced SPs, 1.52 (95% CI, 0.78-2.25) for SPs of ≥10 mm, 5.86 (95% CI, 2.16-9.56) for SPs with dysplasia, 1.18 (95% CI, 0.77-1.60) for proximal SPs, 0.52 (95% CI, 0.08-1.12) for ≥3 SPs, 0.50 (95% CI, 0.35-0.66) for nonadvanced SPs, and 0.44 (95% CI, 0.41-0.46) for normal colonoscopy findings. Metachronous CRC risk was higher in advanced SPs versus nonadvanced SPs (RR, 1.84; 95% CI, 1.11-3.04) and versus normal colonoscopy findings (RR, 2.92; 95% CI, 2.26-3.77), in SPs of ≥10 mm versus <10 mm (RR, 2.61; 95% CI, 1.43-4.77) and versus normal colonoscopy findings (RR: 3.52; 95% CI, 2.17-5.69); and in SPs with dysplasia versus normal colonoscopy findings (RR: 2.71; 95% CI, 2.00-3.67). No increase in CRC or advanced polyp risk was found in patients with proximal versus distal SPs, nor in ≥3 SPs versus 1 or 2 SPs.

CRC risk is significantly higher in patients with baseline advanced SPs after 4.9 years of follow-up, with risk magnitudes similar to those described for AA, supporting the current recommendation for 3-year surveillance in patients with advanced SPs.

A 69-year-old female was presented with a history of sigmoid colon cancer, uterine cancer, and intrahepatic carcinomas. After computed tomography revealed a disseminated nodule located in the peritoneum, colonoscopy demonstrated a rather flat-to-slightly elevated lesion with a depressed area located in the ascending colon. The flat component showed color similar to its surrounding area, and the depressed area showed redness and an expanded appearance. We obtained a biopsy specimen from the depressed area, and microscopic examination revealed well-differentiated adenocarcinoma, which was immunohistochemically positive for BRAF V600E-mutated and PMS2 proteins, and showed loss of MSH2 and MSH6 protein expressions. These findings suggested the lesion to have transformed from a sessile serrated lesion (SSL) to mismatch repair (MMR) deficient colon cancer. The patient underwent surgical removal of the nodule, which interpreted as metastasis of intrahepatic cholangiocarcinoma histopathologically. After postoperative chemotherapy, the follow-up colonoscopy revealed only the flat portion of the lesion without depressed area. Consequently, we performed an endoscopic resection, and microscopic examination confirmed the existence of BRAF V600E-mutated protein-positive and MMR protein-retained SSL without residual carcinoma. This is the first report of BRAF-mutant and MMR-deficient colon cancer, in association with SSL, showing regression.

Colorectal cancer (CRC) is the second most deadly cancer globally. The rapidly rising incidence rate of CRC, coupled with increased diagnoses in individuals <50 years, indicates that early detection of CRC, and those at an increased risk of CRC development, is paramount to improve the survival rates of these patients. Here, we profile caspase-4 expression across 2 distinct CRC development pathways, sporadic CRC (sCRC) and inflammatory bowel disease-associated CRC (IBD-CRC), to examine its utility as a novel biomarker for CRC risk and diagnosis.

Tissue samples from patients with CRC, colonic polyps, IBD-CRC, and sCRC were assessed by immunohistochemistry for caspase-4 expression in epithelial and stromal compartments. RNAseq expression data for caspase-4 in CRC and normal tissue samples were mined from online databases.

Epithelial caspase-4 expression is selectively elevated in CRC tumor tissue compared to adjacent normal tissue, where it is not expressed. In the sCRC pathway, caspase-4 is expressed in the epithelial and stromal tissue of all histological subtypes of colonic polyps, with a significant increase in epithelial expression from low-grade dysplasia to high-grade dysplasia progression. For the IBD-CRC pathway, caspase-4 epithelial expression was specifically upregulated in dysplastic and neoplastic tissue of IBD-CRC but was not expressed in normal or inflamed tissue.

This study demonstrates that epithelial caspase-4 is selectively expressed in colon tissue during the development of dysplasia. As such, epithelial caspase-4 represents a promising novel tissue biomarker for CRC risk and diagnosis.

The incidence and mortality of colorectal cancer (CRC) in China are increasing in recent years. The clarified pathogenesis and detectable precancerous lesions of CRC make it possible to prevent, screen, and diagnose CRC at an early stage. With the development of endoscopic and surgical techniques, the choice of treatment for early CRC is also worth further discussion, and accordingly, a standard follow-up program after treatment needs to be established.

This clinical practice guideline (CPG) was developed following the recommended process of the World Health Organization, adopting Grading of Recommendations Assessment, Development and Evaluation (GRADE) in assessing evidence quality, and using the Evidence to Decision framework to formulate clinical recommendations, thereby minimizing bias and increasing transparency of the CPG development process. We used the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement and Appraisal of Guidelines for Research and Evaluation II (AGREE II) as reporting and conduct guides to ensure the guideline's completeness and transparency.

This CPG comprises 46 recommendations concerning prevention, screening, diagnosis, treatment, and surveillance of CRC. In these recommendations, we have indicated protective and risk factors for CRC and made recommendations for chemoprevention. We proposed a suitable screening program for CRC based on the Chinese context. We also provided normative statements for the diagnosis, treatment, and surveillance of CRC based on existing clinical evidence and guidelines.

The 46 recommendations in this CPG are formed with consideration for stakeholders' values and preferences, feasibility, and acceptability. Recommendations are generalizable to resource-limited settings with similar CRC epidemiology pattern as China.

Identifying molecular alterations in the adenoma and carcinoma components within the same tumor would greatly contribute to understanding the neoplastic progression of early colorectal cancer.

We examined somatic copy number alterations (SCNAs) and mutations involved in the adenoma and carcinoma components obtained from the same tumor in 46 cases of microsatellite-stable carcinoma in adenoma, using a genome-wide SNP array and gene mutation panel. In addition, we also performed hierarchical clustering to determine the SCNA frequencies in the tumors, resulting in stratification of the samples into two subgroups according to SCNA frequency. Subgroup 1 was characterized by multiple SCNAs and carcinoma components exclusively, while Subgroup 2 was characterized by a low frequency of SCNAs and both the adenoma and carcinoma components. The numbers of total genes and genes with gains were higher in the carcinoma than adenoma components. The three most frequent gains in both components were located at 1p36.33-1q44, 2p25.3-2q37.3, and 3p26.3-3q29. However, no candidate genes mapped to these regions. APC and KRAS mutations were common in both components, whereas the frequency of TP53 mutations was statistically higher in the carcinoma than adenoma component. However, TP53 mutations were not correlated with SCNA frequency.

We suggest that considerable SCNAs and TP53 mutations are required for progression from adenoma to carcinoma within the same intramucosal neoplastic lesion.

During endoscopy, white spots (WS) are sometimes observed around benign or malignant colorectal tumors; however, few reports have investigated WS, and their significance remains unknown. Therefore, we investigated the significance of WS from clinical and pathological viewpoints and evaluated its usefulness in endoscopic diagnosis.

Clinical data of patients with lesions diagnosed as epithelial tumors from January 1, 2019, to December 31, 2020, were analyzed (n=3,869). We also performed a clinicopathological analysis of adenomas or carcinomas treated with endoscopic resection (n=759). Subsequently, detailed pathological observations of the WS were performed.

The positivity rates for WS were 9.3% (3,869 lesions including advanced cancer and non-adenoma/carcinoma) and 25% (759 lesions limited to adenoma and early carcinoma). Analysis of 759 lesions showed that the WS-positive lesion group had a higher proportion of cancer cases and larger tumor diameters than the WS-negative group. Multiple logistic analysis revealed the following three statistically significant risk factors for carcinogenesis: positive WS, flat lesions, and tumor diameter ≥5 mm. Pathological analysis revealed that WS were macrophages that phagocytosed fat and mucus and were white primarily because of fat.

WS are cancer-related findings and can become a new criterion for endoscopic resection in the future.

Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally. It's recognized that the molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines the current molecular classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like syndrome (LLS), and sporadic cases. Despite advances in understanding of these genetic backgrounds, clinical trials have not conclusively differentiated the efficacy of immune checkpoint inhibitors among these subgroups. Therefore, while this review details the molecular characteristics and their general implications for treatment and prognosis, it also highlights the limitations and the need for more refined clinical studies to ascertain tailored therapeutic strategies for each subtype. Furthermore, this review summarizes completed and ongoing clinical studies, emphasizing the importance of developing treatments aligned more closely with molecular profiles. By discussing these aspects, the review seeks to provide a comprehensive analysis of oncological characteristics, presenting a detailed understanding of their implications for treatment and prognosis in dMMR/MSI-H CRC.

Inflammatory factors play an important role in the onset and progression of colorectal cancer (CRC). This study aimed to develop and validate a novel scoring system that utilizes specific inflammatory factor indicators to predict intestinal obstruction in CRC patients.

This study conducted a retrospective analysis of 1,470 CRC patients who underwent surgical resection between January 2013 and July 2018. These patients were randomly allocated to the training group (n = 1060) and the validation group (n = 410). Univariate and multivariate logistic regression analyses were performed to identify independent predictive factors for intestinal obstruction. The CRC peculiar inflammation score (CPIS), comprising lymphocyte-to-monocyte ratio (LMR), prognostic nutrition index (PNI), and alanine transaminase-to-lymphocyte ratio index (ALRI) scores, was significantly associated with the occurrence of intestinal obstruction. A nomogram combining CPIS with other clinical features was developed to predict this occurrence. Model accuracy was assessed by determining the area under the receiver operating characteristic (ROC) curve (AUC).

The CPIS generated by multi-factor logistic regression was as follows: - 1.576 × LMR - 0.067 × PNI + 0.018 × ALRI. Using CPIS cutoff values of 50% (- 7.188) and 85% (- 6.144), three predictive groups were established. Patients with a high CPIS had a significantly higher risk of intestinal obstruction than those with a low CPIS (odds ratio [OR]: 10.0, confidence interval [CI]: 5.85-17.08, P < 0.001). The predictive nomogram demonstrated good calibration and discrimination abilities. The AUC of the ROC curve for the obstruction nomogram was 0.813 (95% CI: 0.777-0.850) in the training set and 0.806 (95% CI: 0.752-0.860) in the validation set. The calibration curve exhibited neither bias nor high credibility. Decision curve analysis indicated the utility of this predictive model.

CRC-associated intestinal obstruction is closely linked to inflammatory markers in patients. CPIS is a CRC-specific inflammatory predictive score based on a combination of inflammatory-related indicators. A high CPIS serves as a strong indicator of intestinal obstruction. Its integration with other clinical factors and preoperative inflammatory-specific indicators significantly enhances the diagnosis and treatment of CRC patients with intestinal obstruction.

The colorectal adenoma undergoes neoplastic progression via the normal epithelium-adenoma-adenocarcinoma sequence as reported in the Vogelgram. The hazard of developing a tumor is deeply associated with the number and size of adenomas and their subtype. Adenomatous polyps are histologically categorized as follows: approximately 80-90% are tubular, 5-15% are villous, and 5-10% are tubular/villous. Given the higher risk of a malignant transformation observed in tubular/villous adenomas, patients diagnosed with adenomatous polyposis are at an improved risk of developing CRC. The Wnt/β-catenin pathway plays a key role in the onset of colorectal adenoma; in particular, intestinal cells first acquire loss-of-function mutations in the APC gene that induce the formation of adenomas.

Wnt/β-catenin pathway APC, Wnt3a, Wnt5a, LEF1, and BCL9 genes and protein expression analyses were conducted by qRT-PCR and western blot in 68 colonic samples (polyps and adjacent mucosa) from 41 patients, of which 17 were affected by FAP. Ten normal colonic mucosal samples were collected from 10 healthy donors.

In this study, both the APC gene and protein were less expressed in the colon tumor compared to the adjacent colonic mucosa. Conversely, the activated β-catenin was more expressed in polyps than in the adjacent mucosa. All results confirmed the literature data on carcinomas. A statistically significant correlation between Wnt3a and BCL9 both in polyps and in the adjacent mucosa underlines that the canonical Wnt pathway is activated in early colon carcinogenesis and that the adjacent mucosa is already altered.

This is the first study analyzing the difference in expression of the Wnt/β-catenin pathway in human colorectal adenomas. Understanding the progression from adenomas to colorectal carcinomas is essential for the development of new therapeutic strategies and improving clinical outcomes with the use of APC and β-catenin as biomarkers.

Colorectal cancer (CRC) has the highest mortality rate among men and is the second highest among women under fifty, with incidence and mortality rates rising in younger populations. Studies indicate that up to one-third of patients diagnosed before fifty have a family history or genetic factors, highlighting the need for earlier screening. Contrariwise, diagnosis in healthy subjects through screening strategies enables early-stage detection of the tumor and better clinical outcomes. In recent years, mortality rates of CRC in Western countries have been on a steady decline, which is largely attributed to widespread screening programs and advancements in treatment modalities. Indeed, early detection through screening significantly improves prognosis, with stark differences in survival rates between localized and metastatic disease. This article aims to provide a comprehensive review of the existing literature, delving into the performance and efficacy of various CRC screening strategies. It navigates through available screening tools, evaluating their efficacy and cost-effectiveness. The discussion extends to delineating target populations for screening, emphasizing the importance of tailored approaches for individuals at heightened risk.

Serrated lesions and polyps (SP) are precursors of up to 30 % of colorectal cancers (CRC) through the serrated pathway. This often entails early BRAF mutations and MLH1 hypermethylation leading to mismatch repair deficient (dMMR) CRC. We investigated predictors of dMMR CRC among patients with co-occurrence of CRC and SP to increase our knowledge on the serrated pathway.

We used data from The Danish Pathology Registry and Danish Colorectal Cancer Groups Database from the period 2010-2021 to investigate risk factors for development of dMMR CRC. We used logistic regression models to identify difference in risk factors of developing dMMR CRC in comparison to CRC with proficient MMR (pMMR).

We included 3273 patients with a median age of 70.7 years [64.3,76.4] of which 1850 (56.5 %) were male. dMMR CRC was present in 592 patients (18.1 %), with loss of MLH1/PMS2 being most common. The risk of dMMR CRC was significantly higher in females OR 3.47 [2.87;4.20]. When adjusting for age, SP subtype, conventional adenomas (CA), anatomical location and lifestyle factors, female sex remained the strongest predictor OR 2.84 [2.27;3.56]. The presence of sessile serrated lesions with or without dysplasia was related to higher risk OR 1.60 [1.11;2.31] and OR 1.42 [1.11;1.82] respectively, while conventional adenomas constituted a lower risk OR 0.68 [0.55;0.84].

In conclusion we found several predictors of whom female sex had the strongest correlation with dMMR CRC in patients with SP.

Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15-20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease.

This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP.

This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples.

This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.

Diagnostic ability of sessile serrated lesions (SSL) and SSL with dysplasia (SSLD) using blue laser/light imaging (BLI) has not been well examined. We analyzed the diagnostic accuracy of BLI for SSL and SSLD using several endoscopic findings compared to those of narrow band imaging (NBI).

This was a subgroup analysis of prospective studies. 476 suspiciously serrated lesions of ≥2 mm on the proximal colon showing serrated change with magnified NBI or BLI in our institution between 2014 and 2021 were examined histopathologically. After propensity score matching, we evaluated the diagnostic ability of SSL and SSLD of the NBI and BLI groups regarding various endoscopic findings. For WLI findings, granule, depression, and reddish were examined for diagnosing SSLD. For NBI/BLI findings, expanded crypt opening (ECO) or thick and branched vessels (TBV) were examined for diagnosing SSL. Network vessels (NV) and white dendritic change (WDC) defined originally were examined for diagnosing SSLD.

Among matched 176 lesions, the sensitivity of lesions with either ECO or TBV for SSL in the NBI/BLI group was 97.5%/98.5% (p = 0.668). Those with either WDC or NV for diagnosing SSLD in the groups were 81.0%/88.9% (p = 0.667). Regarding the rates of endoscopic findings among 30 SSLD and 290 SSL, there were significant differences in WDC (66.4% vs. 8.6%, p < 0.001), NV (55.3% vs. 1.4%, p < 0.001), and either WDC or NV (86.8% vs. 9.0%, p < 0.001).

The diagnostic ability of BLI for SSL and SSLD was not different from NBI. NV and WDC were useful for diagnosing SSLD.

High-risk adenomas predict metachronous advanced adenomatous neoplasia. Limited data exist on predictors of metachronous advanced serrated lesions (mASLs). We analyzed clinical and endoscopic predictors of mASLs.

In this retrospective cohort study, adults with >1 outpatient colonoscopy between 2008 and 2019 at a tertiary center were included. Serrated lesions (SLs) included sessile SLs (SSLs), traditional serrated adenomas (TSAs), and hyperplastic polyps (HPs). Patient and endoscopic characteristics were obtained using electronic medical records. Five-year cumulative incidence of mASL (HP ≥10 mm, SSL ≥10 mm or with dysplasia, any TSA) and factors associated with mASL were evaluated using Kaplan-Meier estimates and Cox proportional hazards models.

A total of 4990 patients were included and 45.4% were women. Mean age was 60.9 ± 9.2 years and median follow-up time was 3.7 years. Female sex and active smoking were associated with mASL. Endoscopically, any SSL and TSA were associated with mASL. The 5-year cumulative incidence for mASL was 26% (95% confidence interval [CI], 18%-32%) for SSL ≥10 mm, 17% (95% CI, 3.5%-29%) for HP ≥10 mm, 21% (95% CI, 0%-42%) for 3-4 SSLs <10 mm, 18% (95% CI, 0%-38%) for TSA, and 27% (95% CI, 3.6%-45%) for SSL with low-grade dysplasia. Baseline synchronous nonadvanced SL and nonadvanced adenoma were not associated with mASL.

Our data support current recommendations for a 3-year surveillance interval in patients with baseline SSL ≥10 mm, SSL with dysplasia, and TSA. A 3-year interval may be more appropriate than 3-5 years for patients with baseline HP ≥10 mm or 3-4 SSLs <10 mm. Patients with synchronous nonadvanced SLs and adenomas do not appear to be at increased risk of mASL.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Over the past three decades, extensive efforts have sought to elucidate the genomic landscape of CRC. These studies reveal that CRC is highly heterogeneous at the molecular level, with different subtypes characterised by distinct somatic mutational profiles, epigenetic aberrations and transcriptomic signatures. This review summarises our current understanding of the genomic and epigenomic alterations implicated in CRC development and progression. Particular focus is given to how characterisation of CRC genomes is leading to more personalised approaches to diagnosis and treatment.

Background and study aims Serrated lesions have been identified as precursor lesions for 20% to 35% of colorectal cancers (CRCs) and may contribute to a significant proportion of interval-cancer. Sessile-serrated-lesions (SSLs), in particular, tend to be flat and located in the proximal colon, making their detection challenging and requiring expertise. It remains unclear whether the detection rate for serrated polyps should be considered as a quality indicator in addition to the adenoma detection rate (ADR). This study sought to assess whether the ADR has an effect on the detection rate for serrated polyps. atients and methods In this retrospective analysis, prospectively collected data from 212,668 screening colonoscopies performed between 2012 and September 2018 were included. Spearman correlation and Whitney-Mann U-test were used to assess the association of ADR and the detection rate of SSLs with (SDR) and without hyperplastic polyps (SPADRs), the sessile serrated detection rate (SSLDR) as well as the clinically relevant serrated detection rate (CRSDR), including all SSLs and traditional serrated adenoma, hyperplastic polyps (HPs) >10 mm anywhere in the colon or HPs > 5 mm proximal to the sigmoid. Results The overall mean ADR was 21.78% (standard deviation [SD] 9.27), SDR 21.08% (SD 11.44), SPADR 2.19% (SD 2.49), and CRSDR was 3.81% (3.40). Significant correlations were found between the ADR and the SDR, SPADR, SSLDR, and CRSDR (rho=0.73 vs. rho=0.51 vs. rho=0.51 vs. rho=0.63; all P <0.001). Endoscopists with a mean ADR ≥25% had significantly higher SDR, SPADR, and CRSDR than endoscopists with a mean ADR <25% (all P <0.001; Mann-Whitney U-Test). Conclusions This study shows that endoscopists with higher ADR detect significantly more serrated lesions than those with a lower ADR.