Colorectal cancer (CRC) is the third most common cancer in Denmark, with a 5-year mortality of 40%. To reduce CRC incidence and mortality, a faecal immunochemical test (FIT)-based screening programme was introduced in 2014. Adenoma detection rate (ADR) is an established quality marker inversely associated with post-colonoscopy CRC (PCCRC), but evidence mainly stems from non-FIT populations. Using ADR in a FIT-based setting may be costly due to histopathological examination. Alternative markers like polyp detection rate (PDR) and sessile serrated lesion detection rate (SDR) could be viable but lack evidence for their association with PCCRC.

We conducted a nationwide cohort study of 77 009 FIT-positive participants undergoing colonoscopy (2014-2017). National registry data on CRC outcomes were linked, and endoscopy units were grouped by ADR, PDR and SDR levels. Poisson regression adjusted for age, sex and comorbidities was used to assess PCCRC risk.

Among 70 009 colonoscopies within 6 months of FIT positivity, 4401 (92.7%) had CRC, while 342 (7.2%) were PCCRC cases. PCCRC risk was inversely associated with ADR, PDR and SDR. High ADR endoscopy units had a 35% lower PCCRC risk than low ADR units. Similar associations were found for PDR and SDR, with high SDR units showing a 33% lower PCCRC risk than low SDR units.

ADR, PDR and SDR predict PCCRC risk, with SDR emerging as a feasible, cost-efficient quality marker in FIT-based screening. This study supports SDR as a primary performance indicator in future protocols.

The histological assessment of colorectal precancer and cancer lesions is challenging and primarily impacts the clinical strategies of secondary colon cancer prevention. Artificial intelligence (AI) models may potentially assist in the histological diagnosis of this spectrum of phenotypical changes.

To provide a current overview of the evidence on AI-based methods for histologically assessing colonic precancer and cancer lesions.

Based on the available studies, this review focuses on the reliability of AI-driven models in ranking the histological phenotypes included in colonic oncogenesis.

This review acknowledges the efforts to shift from subjective pathologists-based to more objective AI-based histological phenotyping. However, it also points out significant limitations and areas that require improvement.

Current AI-driven methods have not yet achieved the expected level of clinical effectiveness, and there are still significant ethical concerns that need careful consideration. The integration of "artificial histology" into diagnostic practice requires further efforts to combine advancements in engineering techniques with the expertise of pathologists.

Traditional serrated adenoma (TSA) is a rare and precancerous lesion of colorectal cancer. The clinical and endoscopic differentiations between TSAs without dysplasia or adenocarcinoma (TSAOs) and TSAs with dysplasia or adenocarcinoma (TSADs) remain unclear.

To evaluate the characteristics of colorectal TSAs and compare the characteristics of TSAOs with those of TSADs.

This retrospective study included 193 patients who underwent endoscopic resection and received a pathologic diagnosis of TSA. We reviewed the medical, endoscopic, and histopathologic records of patients who underwent endoscopic resection of TSAs between January 2010 and December 2023.

TSAs were more frequently located in the rectosigmoid colon. Most TSAs had 0-Ip, 0-Isp, or 0-Is morphologies. The TSAD lesions were larger than TSAO lesions. TSAD lesions more commonly had a red color and an irregular border than TSAO lesions. TSAOs were usually treated using conventional endoscopic mucosal resection, whereas TSADs were treated using conventional endoscopic mucosal resection, endoscopic submucosal dissection, and surgery. Post-polypectomy bleeding was more common with TSADs than with TSAOs. Univariate analysis showed that gastrointestinal bleeding, red color, 0-IIa, irregular border, and lobular mucosal surface were significantly associated with TSADs. Multivariate analysis showed that gastrointestinal bleeding, an irregular border, and a lobular mucosal surface were significantly associated with TSADs.

TSAs with gastrointestinal bleeding, an irregular border, and a lobular mucosal surface are associated with an increased risk of dysplasia or adenocarcinoma.

Colorectal cancer (CRC) is the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide, with an increasing shift towards younger age of onset. In recent years, there has been increasing recognition of the significance of tRNA-derived small RNAs (tsRNAs), encompassing tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs). Their involvement in regulating translation, gene expression, reverse transcription, and epigenetics has gradually come to light. Emerging research has revealed dysregulation of tsRNAs in CRC, implicating their role in CRC initiation and progression, and highlighting their potential in early diagnosis, prognosis, and therapeutic strategies. Although the clinical application of tsRNAs is still in its early stages, recent findings highlight a close relationship between the biogenesis and function of tsRNAs, tRNA chemical modifications, and the tumor immune microenvironment (TIME). Additionally, similar to other small RNAs, tsRNAs can be effectively delivered via nanoparticles (NPs). Consequently, future research should focus on elucidating the clinical significance of tsRNAs concerning base modifications, TIME regulation, cancer immunotherapy, and NPs delivery systems to facilitate their clinical translation.

Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is a multifaceted, cytokine-like bioactive molecule whose levels are elevated in a wide range of inflammatory diseases and are associated with prognosis. Additionally, TIMP1 may play a role in driving systemic inflammation. TIMP1 immunohistochemistry and TIMP1 serum concentrations were analyzed in a cohort of 776 colorectal cancer patients. TIMP1 histoscore by cell type (tumor cell, other) was quantified using digital image analysis. Serum TIMP1 levels were evaluated for correlations with tumor TIMP1 expression, and their associations with tumor characteristics, inflammation, and prognosis were investigated. High serum TIMP1 concentrations associated with shorter overall survival (multivariable HR 1.85, 95% CI 1.30-2.65). Serum TIMP1 levels positively correlated with markers of systemic inflammation and tumor necrosis percentage but not with TIMP1 expression in tumor tissue. High TIMP1 intensity in tumor stroma associated with longer cancer-specific and overall survival in univariable analysis but not in multivariable models. T cell densities in tumor tissue positively correlated with tumor stromal TIMP1 expression and negatively with tumor epithelial TIMP1 expression. Serum TIMP1 levels show promise as a prognostic marker for colorectal cancer and correlate with systemic inflammatory markers, but do not correlate with TIMP1 expression in tumor tissue.

Serrated lesions are precursors of some colon cancers. The expression of galectin-3 has been reported to be involved in BRAF and KRAS mutations (the key pathogenic drivers of serrated lesions). This study aimed to investigate the expression intensity and subcellular localization of galectin-3 in serrated colon lesions by immunohistochemistry. The results demonstrated that, regarding expression intensity, galectin-3 expression in serrated colon lesions was significantly upregulated; regarding subcellular localization, the membrane expression of hyperplastic polyps/ sessile serrated lesions (HP/SSL) was weakened, the structure was disorganized and that of traditional serrated adenoma (TSA) was significantly weakened or disappeared, and the nuclear expression of both was positive; in the dysplasia of SSL (SSL-D) and TSA (TSA-HD), galectin-3 expression intensity remained high, and was weakened or disappeared in some nuclei, the expression disorder of the SSL-D cell membrane was reduced, the polarity of the cell was restored, weak expression appeared in the local cell membrane of TSA-HD, and the "serrated" structure of both was reduced or disappeared and seemed to revert more to that seen in common adenomas. In summary, abnormal galectin-3 expression occurs in the early stages of serrated lesions, its expression is characteristic, the dynamic changes in galectin-3 expression are closely related to the histopathological changes and progression of serrated lesions, and further accumulated molecular alterations contribute to this process.

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.

Although inflammatory bowel disease (IBD) and colorectal polyps are considered as significant risk factors of colorectal cancer (CRC), the molecular mechanism associated with colorectal carcinogenesis is still explored. Unlike sporadic CRC, local persistent inflammation in IBD induces genetic and epigenetic alterations, leading to tumor development. Moreover, cumulative data indicate that colorectal polyps display a significant malignant potential. In this context, our study aimed to investigate the clinicopathological features of CRC associated with IBD and/or colorectal neoplastic polyps in a retrospective group of CRC cases. The clinical data and histopathological features of CRC cases have been collected from our files. Immunohistochemical examination of mismatch repair (MMR) proteins has been performed in a selected case. The study group comprised 40 patients, 72.5% men and 27.5% women, with a median age of 64.73±9.09 years. Out of the cases with double association, 62.5% of CRC cases displayed colorectal polyps, while 32.5% of patients were diagnosed with both CRC and IBD, which encompassed both ulcerative colitis (UC) and Crohn's disease (CD). Two patients included in our study group exhibited a triple association of IBD, colorectal polyps, and CRC, one of them showing defective MMR (dMMR) phenotype. Although our results provide significant data on the relationship between IBD, colorectal polyps, and colorectal carcinogenesis, future cohort studies are needed to improve our understanding on the complex mechanism of colorectal carcinogenesis, ultimately guiding improved prevention, diagnosis, and treatment strategies for these patients.

Evidence indicates that combinations of anti-EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)-low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS-wild-type tumors (31%). KRAS c.34G>T mutants showed higher CIMP-high prevalence (14%) and lower CIMP-negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T-mutated tumors were associated with cecal location, non-microsatellite instability (MSI)-high status, BRAF wild type, and PIK3CA mutation when compared with KRAS-wild-type tumors. Compared with BRAF-mutated tumors, KRAS c.34G>T mutants showed more frequent LINE-1 hypomethylation, a biomarker for early-onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks+ Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF-wild-type colorectal carcinomas, compared with KRAS-wild-type tumors, multivariable-adjusted colorectal cancer-specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05-3.17) in KRAS c.34G>T (p.G12C)-mutated tumors (p = 0.035) and 1.57 (1.22-2.02) in other KRAS-mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma.

Colon cancer (CC) stands as one of the most common malignancies related to the gastrointestinal system, whose increasing incidence and death rates have been reported all over the world. Standard treatments for fighting cancers like CC comprise surgical approaches, chemotherapy, and radiotherapy, which are suggested by clinicians according to patients' conditions and disease stages. However, patients who utilize these modalities may suffer from serious side effects and adverse outcomes, for example, toxicity and tumor recurrence, as well as a low 5-year survival rate. The present shreds of evidence showed that mesenchymal stem cells (MSCs) can have a suitable capacity for treating different health problems, especially neoplasms. These multipotent stem cells can be isolated from several sources, such as the umbilical cord, bone marrow, adipose tissue, and placenta. Among these mesenchymal sources, umbilical cord-MSCs have gathered much attention in scientific societies due to their advantages (e.g., low immunogenicity, lack of ethical problems, and easy collection). These days, the efficacy of umbilical cord-MSCs and umbilical cord-MSCs-based strategies, such as conditioned medium, extracellular vesicles, and exosomes, on CC have been explored, and promising findings have been stated. Therefore, in this review, we aimed to summarize and debate evidence regarding the effects of UC-MSCs and their related products on CC with a focus on molecular and cellular mechanisms involved in its treatment and pathogenesis of this malignant tumor.

Data regarding the status of the vertical margin of sessile serrated lesions (SSLs) resected using cold snare polypectomy (CSP) are lacking, and whether a histopathologically positive vertical margin is related to recurrence remains unclear. Therefore, this preliminary study aimed to clarify the rates of positive or unassessable vertical and horizontal margins and the rate of muscularis mucosae resection in SSLs treated using CSP compared with those treated with EMR.

Histologic outcomes of patients treated with CSP or EMR for SSLs were evaluated in this single-center observational study. The primary outcome was the incidence of histopathologically positive vertical margins in CSP and EMR. Furthermore, the comparisons were adjusted for confounding factors using propensity score matching.

Overall, 82 patients with SSLs were included in the CSP and EMR groups after matching. The incidence of positive histologic vertical margins in the CSP and EMR groups were 67.1% and 2.4%, respectively (P < .001). Regarding the evaluation of the presence of muscularis mucosae, 29.3% and 98.8% of patients in the CSP and EMR groups, respectively, had a complete muscularis mucosae resection (P < .001).

A rigorous histopathologic evaluation revealed that for SSLs, CSP more frequently leads to positive vertical margins than EMR. (Clinical trial registration number: UMIN 000051569.).

Colorectal cancer is a highly prevalent malignancy and a significant driver of cancer mortality and health-related expenditure worldwide. Polyp removal reduces the incidence and mortality of colorectal cancer. In 2024, endoscopists have an array of resection modalities at their disposal. Each technique requires a unique skillset and has individual advantages and limitations. Consequently, resection in the colorectum requires an evidence-based algorithm approach that considers these factors.

A literature review of endoscopic resection for colonic neoplasia was conducted. Best supporting scientific evidence was summarized for the endoscopic resection of diminutive polyps, large ≥20 mm lesions and polyps containing invasive cancer. Factors including resection modality, complications and lesion selection were explored to inform an algorithm approach to colorectal resection.

Endoscopic resection in the colorectum is not a one-size-fits-all approach. Detailed understanding of polyp size, location, morphology and predicted histology are critical factors that inform appropriate endoscopic resection practice.

High perforation risk hinders the widespread adoption of ESD for colorectal neoplasms. This study was performed to determine the risk factors of colorectal endoscopic submucosal dissection (ESD)-induced perforation and develop a predictive model.

A total of 1046 colorectal neoplasms in 1011 patients were retrospectively enrolled from January 2011 to December 2021, in a single tertiary center as the derivation cohort. We identified independent risk factors for perforation using univariate analysis and multi-variate logistic regression. A nomogram was developed based on the logistic regression model and prospectively applied to 266 colorectal neoplasms as the validation cohort. The performance of the predictive model was evaluated with the receiver operating characteristic curve, calibration plot, and decision curve analysis.

Independent pre-operative factors for colorectal ESD-induced perforation were tumor located in the left colon [odds ratio (OR) 2.39, P = 0.040], size ≥ 40 mm (OR 3.36, P < 0.001), ≥2/3 circumference (OR 7.55, P = 0.004), located across folds (OR 6.26, P < 0.001), and laterally spreading tumor (non-granular type, OR 2.34, P = 0.029; granular type, OR 2.46, P = 0.021). The nomogram model incorporating the pre-operative factors performed well in both the derivation and validation cohorts (areas under the curve of 0.750 and 0.806, respectively). Decision curve analysis demonstrated that the clinical benefit of the nomogram was favorable.

The novel nomogram, developed and prospectively validated, incorporating tumor size, location, and morphology can successfully predict perforation during ESD for colorectal neoplasms.

Cancer stem cells (CSCs) are a long-lived and self-renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5+ CSCs as well as quiescent Lgr5+ CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC.

Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes.

We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC.

In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent.

A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.

Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Sessile serrated lesions (SSLs) are precursors of sporadic colorectal cancer (CRC) and have distinct characteristics compared with conventional adenomas (CAs). Several lifestyle and environmental factors may play critical roles in the development of advanced lesions. Our aim is to describe the features of SSLs and CAs and further explore risk factors for advanced lesions.

This is an observational study that collected demographic, endoscopic, and histological data from the China-Japan Friendship Hospital among the inpatient population with pathologically reported as SSL or CA between 2015 and 2022. We analyzed the clinicopathology and endoscopic differences between SSL alone, CA alone, and synchronous SSL+CA groups, and identified risk factors using multiple regression analysis.

A total of 9236 polyps from 6598 patients were included in the cohort. Patients with SSL+CA were more likely to be older (p=0.008), while individuals with SSL alone had a higher proportion of early-onset polyps (p<0.001), and SSLs were more common in advanced polyps than CAs (p<0.001). A greater proportion of advanced polyps in the SSL and CA groups were diagnosed as Yamada III, Yamada IV, and laterally spreading tumor (p=0.002, p<0.001, respectively), and multiple SSLs and CAs were more represented in nonadvanced polyps than in advanced polyps. In multiple regression analysis, older patients were more likely to develop advanced SSLs (aOR 1.05, 95% CI 1.02-1.09, p=0.005).

SSLs and CAs have diverse demographic, endoscopic, and histological characteristics, and their advanced lesions share different risk factors, which advances the understanding of the etiology and progression of SSLs.

The serrated pathway to colorectal cancers (CRCs) is a significant pathway encompassing five distinct types of lesions, namely hyperplastic polyps (HPs), sessile serrated lesions (SSLs), sessile serrated lesions with dysplasia (SSL-Ds), traditional serrated adenomas (TSAs), and serrated adenoma unclassified. In contrast to the conventional adenoma-carcinoma pathway, the serrated pathway primarily involves two mechanisms: BRAF/KRAS mutations and CpG island methylator phenotype (CIMP). HPs are the most prevalent non-malignant lesions, while SSLs play a crucial role as precursors to CRCs, On the other hand, traditional serrated adenomas (TSAs) are the least frequently encountered subtype, also serving as precursors to CRCs. It is crucial to differentiate these lesions based on their unique morphological characteristics observed in histology and colonoscopy, as the identification and management of these serrated lesions significantly impact colorectal cancer screening programs. The management of these lesions necessitates the crucial steps of removing premalignant lesions and implementing regular surveillance. This article provides a comprehensive summary of the epidemiology, histologic features, molecular features, and detection methods for various serrated polyps, along with recommendations for their management and surveillance.

Colorectal mucinous adenocarcinoma (MAC) is one of the most lethal histological types of colorectal cancer, and its mechanism of development is not well understood. In this study, we aimed to clarify the molecular characteristics of MAC via in silico analysis using The Cancer Genome Atlas database. The expression of genes on chromosome 20q (Chr20q) was negatively associated with the expression of MUC2, which is a key molecule that can be used to distinguish between MAC and nonmucinous adenocarcinoma (NMAC). This was consistent with a significant difference in copy number alteration of Chr20q between the two histological types. We further identified 475 differentially expressed genes (DEGs) between MAC and NMAC, and some of the Chr20q genes among the DEGs are considered to be pivotal genes used to define MAC. Both in vitro and in vivo analysis showed that simultaneous knockdown of POFUT1 and PLAGL2, both of which are located on Chr20q, promoted MUC2 expression. Moreover, these genes were highly expressed in NMAC but not in MAC according to the results of immunohistological studies using human samples. In conclusion, POFUT1 and PLAGL2 are considered to be important for defining MAC, and these genes are associated with MUC2 expression.

Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions.

SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112).

SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components.

Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and is associated with high morbidity and mortality rates. Colorectal carcinogenesis occurs via the conventional adenoma-to-carcinoma and serrated pathways. Conventional T helper (Th) and innate lymphoid cells (ILCs) play vital roles in maintaining intestinal homeostasis. However, the contribution of these two major lymphoid cell populations and their associated cytokines to CRC development is unclear. Therefore, we aimed to analyze peripheral lymphocyte profiles during colorectal carcinogenesis.

We collected 86 blood samples concurrently, and pathologists confirmed the presence of various pathological conditions (i.e., HPs, adenoma, and carcinoma) using hematoxylin and eosin staining. Ten healthy donors were recruited as healthy controls (HCs) from the physical examination center. We performed flow cytometry on peripheral blood mononuclear cells collected from patients with various pathological conditions and the HCs, and cytokines (interleukin-2, interleukin-4, interleukin-5, interleukin-13, interleukin-17A, interleukin-17F, interleukin-22, interferon-γ, and tumor necrosis factor-α) were quantified. We also analyzed the published single-cell RNA sequence data derived from tissue samples from different stages of colorectal carcinogenesis.

The cytokine response in peripheral CD4+ T cells was upregulated during the carcinoma process. The frequency of peripheral regulatory T cells (Tregs) increased in the adenoma and carcinoma stages. While the T follicular helper (Tfh) cell proportion was downregulated in the adenoma and carcinoma processes. Thus, Th cell subsets, especially Tregs and Tfh cells, were involved in colonic diseases. Moreover, the immunological profile characteristics in the HPs were clarified.

We comprehensively analyzed circulating ILCs and adaptive T-cell lymphocyte subtypes in colorectal carcinoma progression. Our results show the immunological profile characteristics and support the involvement of Th subsets, especially Treg and Tfh cell populations, in colonic diseases. These findings significantly enhance our understanding of the immune mechanisms underlying CRC and its precancerous lesions. Further investigation of the Treg and Tfh cells' function in colorectal disease development will provide potential therapeutic targets for monitoring and preventing CRC development.

Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64[CI 2.37-5.58]) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21[CI 2.47-7.15]), or a combination of the two (OR 3.35[CI 2.47-4.53]). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (p < 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (p < 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.

Serrated lesions outside the low digestive tract are scarce, with only two traditional serrated adenomas (TSA) reported in the gallbladder, with limited information about the serrated pathway outside the colon. Our case was an incidental finding in a patient undergoing surgery to treat a cholecystitis, when a polypoid lesion was observed. The epithelium formed gland structures with ectopic crypts, serrated slits and eosinophilic cytoplasm. MUC4 and MUC5A were positive, but mismatch repair proteins (MSI) retained nuclear staining. BRAF showed a not mutated profile and NRAS/KRAS was inconclusive due to the absence of remaining tissue. MSI and CpG island (CIMP), the most common genetic hallmarks of the serrated pathway, have been proven in gallbladder carcinomas, although serrated polyps are not recognized as premalignant precursors. Hereby we report one TSA of the gallbladder without the usual genetic drivers. A larger evidence is needed to improve the diagnosis and management.

The serrated neoplasia pathway constitutes an "alternative route" to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10-15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.