Adenoma-carcinoma Sequence Research Articles

Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids.

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.

Prevalence of colorectal polyps in patients undergoing colonoscopy in Sulaimaniyah gastroenterology center: a retrospective study

Background & objectives: Colorectal cancers are believed to develop primarily through an adenoma-carcinoma sequence, with adenomatous polyps beginning as the primary precursor lesions. Thus, this study aimed to assess the prevalence of colorectal polyps with their characteristics and relation to age/gender and to aid in establishing a screening program to detect polyps and colorectal cancer in the early stages. Methods: In this retrospective study, the data of 2698 patients who underwent colonoscopy in Sulaimani Gastroenterology Center, Sulaimaniyah, Iraq, for various complaints and asymptomatic patients from January 2019 to February 2021 were studied regarding colorectal polyps. Patients sociodemographic data (age, gender, and residency), presented symptoms, surveillance rate for colon cancer and polyps, and disease follow-up were studied. Briefly, patients were given bowel preparation solutions the day before the colonoscopy, and the process was performed under conscious sedation. Results: The mean±SD age of patients was 52.0±17.59 years, and most were females (55.1%)(p=0.000) and from urban areas (62.12%) (p?0.05). Among the studied patients, 14.3% were diagnosed with polyps, of which 17.1% were males and 12.1% were females. The high prevalence rate was found in patients aged >60 years (23.8%), followed by 50-60 years (17.71%), and then 40-49 years (13.07%). Conclusion: Colorectal polyp was common among patients undergoing colonoscopy for several gastrointestinal symptoms, especially after the age of forty.

Comprehensive Analyses of Somatic Copy Number Alterations and Mutations Based on the Adenoma-Carcinoma Sequence.

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.

From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies.

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.

Both Th1 and Th2 CD4 + T-Cell Lineage Infiltrations Decrease in Post-hematopoietic Stem Cell Transplantation Colon Adenoma.

As long-term survival improves after allogeneic hematopoietic stem cell transplantation (HSCT), the risk for secondary solid cancers, including colon cancer, also increases. However, the pathogenesis of secondary solid cancers in post-HSCT patients remains unclear. This study aimed to investigate the involvement of local immunity in colon carcinogenesis in post-HSCT patients by assessing the infiltrating T cells in colon adenomas as premalignant lesions of colon cancer in adenoma-carcinoma sequence. Colon adenoma samples obtained from 19 post-HSCT patients and 57 non-HSCT participants were analyzed via immunohistochemistry. Double staining of CD4/T-bet, CD4/GATA3, and CD4/FoxP3 was performed for evaluation of helper T-cell lineages (Th1, Th2, and regulatory T cells, respectively) and CD8 staining for CD8+ T cells. There were no significant between-group differences in the number of infiltrating CD4+ T cells and CD8+ T cells in adenomas. However, the number of both CD4+/T-bet+ and CD4+/GATA3+ T cells was significantly lower in the post-HSCT adenomas than in the non-HSCT adenomas (P = 0.0171 and 0.0009, respectively), whereas no significant differences were found in the number of CD4+/FoxP3+ cells. Although the number of infiltrating CD4+ and CD8+ T cells, and even Treg cell counts, is sufficiently recovered post-HSCT, CD4+ T-cell dysfunction due to suppressed activation and differentiation in colon adenomas might be involved in colon carcinogenesis in post-HSCT patients. Elucidating the pathogenesis will contribute to the development of effective screening and prevention programs for secondary colon cancer in post-HSCT patients.

Distinct gut microbiomes in Thai patients with colorectal polyps.

Colorectal polyps that develop via the conventional adenoma-carcinoma sequence [e.g., tubular adenoma (TA)] often progress to malignancy and are closely associated with changes in the composition of the gut microbiome. There is limited research concerning the microbial functions and gut microbiomes associated with colorectal polyps that arise through the serrated polyp pathway, such as hyperplastic polyps (HP). Exploration of microbiome alterations associated with HP and TA would improve the understanding of mechanisms by which specific microbes and their metabolic pathways contribute to colorectal carcinogenesis. To investigate gut microbiome signatures, microbial associations, and microbial functions in HP and TA patients. Full-length 16S rRNA sequencing was used to characterize the gut microbiome in stool samples from control participants without polyps [control group (CT), n = 40], patients with HP (n = 52), and patients with TA (n = 60). Significant differences in gut microbiome composition and functional mechanisms were identified between the CT group and patients with HP or TA. Analytical techniques in this study included differential abundance analysis, co-occurrence network analysis, and differential pathway analysis. Colorectal cancer (CRC)-associated bacteria, including Streptococcus gallolyticus (S. gallolyticus), Bacteroides fragilis, and Clostridium symbiosum, were identified as characteristic microbial species in TA patients. Mediterraneibacter gnavus, associated with dysbiosis and gastrointestinal diseases, was significantly differentially abundant in the HP and TA groups. Functional pathway analysis revealed that HP patients exhibited enrichment in the sulfur oxidation pathway exclusively, whereas TA patients showed dominance in pathways related to secondary metabolite biosynthesis (e.g., mevalonate); S. gallolyticus was a major contributor. Co-occurrence network and dynamic network analyses revealed co-occurrence of dysbiosis-associated bacteria in HP patients, whereas TA patients exhibited co-occurrence of CRC-associated bacteria. Furthermore, the co-occurrence of SCFA-producing bacteria was lower in TA patients than HP patients. This study revealed distinct gut microbiome signatures associated with pathways of colorectal polyp development, providing insights concerning the roles of microbial species, functional pathways, and microbial interactions in colorectal carcinogenesis.

TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern

A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors’ database. Among the 16 TPPP-BRD9 fusion-positive GBC cases, most were females (F:M = 7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p < 0.001), all with gastro-pancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC) morphology: 3 cases (27% vs. 4.6% in the reference database, p = 0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remaining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a “syringoid” appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubular-spindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC morphology and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.

Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies

BackgroundEarly detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population.MethodsTo develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants.ResultsThree trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32).ConclusionsOur comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.Graphical

Levels of 5α-reductase gene in intestinal lavage fluid decrease with progression of colorectal cancer.

Introduction. Colorectal cancer (CRC) is a leading cause of cancer deaths, closely linked to the intestinal microbiota and bile acid metabolism. Secondary bile acids, like deoxycholic and lithocholic acid, are associated with increased CRC risk due to their disruption of vital cellular functions. In contrast, isoallolithocholic acid (isoalloLCA) shows potential health benefits, highlighting the complex role of bile acids in CRC. A specific primer set was previously developed to amplify homologs of the 5α-reductase gene (5ar), which are involved in the biosynthesis of isoalloLCA, thereby enabling the estimation of abundance of 5ar (5ar levels) in the intestine.Hypothesis/Gap Statement. We hypothesized that 5ar levels in the intestine are associated with CRC.Aim. This study aimed to investigate intestinal 5ar levels and compare them across different stages of the adenoma-carcinoma sequence, providing insights into novel strategies for monitoring CRC risk.Methodology. DNA was extracted from intestinal lavage fluids (ILF) collected during 144 colonoscopies. Next-generation sequencing (NGS) was employed to examine the sequence of 5ar homologues, using a specific primer set on DNA from seven selected ILFs - four from carcinoma patients and three from individuals with non-neoplastic mucosa. Additionally, we used quantitative PCR (qPCR) to measure 5ar levels in all 144 DNA samples.Results. We conducted 144 colonoscopies and categorized patients according to the adenoma-cancer sequence: 52 with non-neoplastic mucosa, 69 with adenomas and 23 with carcinoma. Analysis of 292,042 NGS-derived 5ar sequences revealed the seven most prevalent amplicon sequence variants, each 254 base pairs in length. These closely matched or were identical to 5ar sequences in Bacteroides uniformis, Phocaeicola vulgatus and Phocaeicola dorei. Furthermore, qPCR analysis demonstrated significantly lower 5ar levels in the carcinoma group compared to those in the non-neoplastic mucosa group (P = 0.0004). A similar, though not statistically significant, trend was observed in the adenoma group (P = 0.0763), suggesting that 5ar levels decrease as CRC progresses.Conclusion. These findings indicate that PCR-based monitoring of 5ar levels in intestinal samples over time could provide a non-invasive, rapid and cost-effective method for assessing an increased risk of CRC.

Histopathological Analysis of Gastrointestinal Polyps: A Yearlong Study at a Tertiary Care Center

This retrospective study was conducted at a tertiary care institute from January to December 2023. The study aimed to evaluate the range of histological characteristics seen in gastrointestinal polyps. By employing Hematoxylin and Eosin (H&amp;E) stained slides, a total of 62 cases were examined in order to categorise polyps according to age, gender, location, and histological type. The results indicated that adenomatous polyps were primarily located in the large intestine, while hyperplastic polyps were more prevalent in the stomach. Additional forms that were detected include hamartomatous, juvenile, fundic gland, inflammatory fibroid, fibroepithelial, retention polyps, and a single case of familial polyposis coli. The study observed a male-to-female ratio of 0.9:1, with the highest number of cases occurring in the age bracket of 61-70. The findings emphasize the significance of differentiating between neoplastic and non-neoplastic polyps, especially because neoplastic polyps can progress through an adenoma-carcinoma sequence. Keywords: Gastrointestinal polyps, adenomatous polyp, hyperplastic polyp

The selective sponging of miRNAs by OIP5-AS1 regulates metabolic reprogramming of pyruvate in adenoma-carcinoma transition of human colorectal cancer

RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC.

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention

AimOur study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA. MethodsFecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve. ResultsOur analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions. ConclusionsThe study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.

Role of MEK1 and DIAPH3 expression in colorectal adenoma-carcinoma sequence.

It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types. The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens. The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique. MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (P = 0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (P = 0.009) and CRA cases (P = 0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (P = 0.050) and perineural invasion (P = 0.017). Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.

Elucidating immunological characteristics of the adenoma-carcinoma sequence in colorectal cancer patients in South Korea using a bioinformatics approach

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan–Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.

Multiple-matrix metabolomics analysis for the distinct detection of colorectal cancer and adenoma.

Although colorectal cancer (CRC) is the leading cause of cancer-related morbidity and mortality, current diagnostic tests for early-stage CRC and colorectal adenoma (CRA) are suboptimal. Therefore, there is an urgent need to explore less invasive screening procedures for CRC and CRA diagnosis. Untargeted gas chromatography-mass spectrometry (GC-MS) metabolic profiling approach was applied to identify candidate metabolites. We performed metabolomics profiling on plasma samples from 412 subjects including 200 CRC patients, 160 CRA patients and 52 normal controls (NC). Among these patients, 45 CRC patients, 152 CRA patients and 50 normal controls had their fecal samples tested simultaneously. Differential metabolites were screened in the adenoma-carcinoma sequence. Three diagnostic models were further developed to identify cancer group, cancer stage, and cancer microsatellite status using those significant metabolites. The three-metabolite-only classifiers used to distinguish the cancer group always keeps the area under the receiver operating characteristic curve (AUC) greater than 0.7. The AUC performance of the classifiers applied to discriminate CRC stage is generally greater than 0.8, and the classifiers used to distinguish microsatellite status of CRC is greater than 0.9. This finding highlights potential early-driver metabolites in CRA and early-stage CRC. We also find potential metabolic markers for discriminating the microsatellite state of CRC. Our study and diagnostic model have potential applications for non-invasive CRC and CRA detection.

Review of Animal Models of Colorectal Cancer in Different Carcinogenesis Pathways.

Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract with increasing morbidity and mortality. Exploring the factors affecting colorectal carcinogenesis and controlling its occurrence at its root is as important as studying post-cancer treatment and management. Establishing ideal animal models of CRC is crucial, which can occur through various pathways, such as adenoma-carcinoma sequence, inflammation-induced carcinogenesis, serrated polyp pathway and de-novo pathway. This article aims to categorize the existing well-established CRC animal models based on different carcinogenesis pathways, and to describe their mechanisms, methods, advantages and limitations using domestic and international literature sources. This will provide suggestions for the selection of animal models in early-stage CRC research.

Abstract 7294: CREATE-2: Colorectal cancer &amp; adenoma test evaluation of a multi-omic blood test

Abstract Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with almost 2 million new cases reported in 2020. CRC develops over time from a pre-cancerous stage (adenoma) - the ‘adenoma-carcinoma sequence’. Pre-cancerous lesions, such as Higher Risk Adenomas (HRA), harbour an increased risk of developing into CRC and their features are defined according to size, number and histological features. Screening for signs of CRC is recommended for average-risk adults using faecal immunochemical testing (FIT) in the UK, to enable the removal of pre-cancerous lesions and treatment of early-stage cancers. However, the performance of FIT is limited. Approximately 10% of CRC diagnoses have a negative FIT result, and it currently has ~93% false positive rate. Moreover, the sensitivity for detecting AA is only 24%, highlighting the need for alternative strategies. Methods: A promising strategy for earlier CRC detection is the clinical use of Fourier transform infrared (FTIR) spectroscopy. The Dxcover® Colorectal Cancer Liquid Biopsy is a rapid multi-omic test that interrogates a blood sample with infrared (IR) radiation and produces a distinctive signature that represents the whole biomolecular profile of the sample. Rather than focusing on individual biomarkers, the technique encompasses the full range of diagnostic information from both the tumor and the non-tumor response. In the initial CREATE (ColoREctal Cancer &amp; Adenoma Test Evaluation) feasibility study, the potential of the technology was highlighted in a retrospective cohort of patients comprising 100 CRC, 92 adenoma samples and 104 colonoscopy screening controls diagnosed as non-cancer. At 90% specificity, the test reported 80% CRC sensitivity and 59% HRA sensitivity. CREATE-2 is a prospective, observational, multicenter study, currently recruiting patients across the United States. The primary objective of the study is to determine the diagnostic accuracy of the blood-based Dxcover Colorectal Cancer Liquid Biopsy for CRC and HRA, and collectively as advanced colorectal neoplasia. Primary outcomes are sensitivity, specificity, negative predictive value, and positive predictive value of the test as compared to the standard of care screening modality. The study population is comprised of patients aged 45-84 considered ‘average-risk’ for CRC, undergoing routine CRC screening as standard of care. Patients are treatment naïve for CRC/HRA and must be willing to consent to blood draw pre-bowel preparation, and follow-up for 24 months. A rapid blood test that is sensitive to pre-cancerous lesions and early-stage CRC could substantially improve patient outcomes. Current screening programs have addressable shortcomings, and the emergence of new technologies is essential to support earlier CRC detection. Citation Format: James M. Cameron, Georgios Antoniou, Rose McHardy, David Palmer, Alexandra Sala, Matthew Baker. CREATE-2: Colorectal cancer &amp; adenoma test evaluation of a multi-omic blood test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7294.

Machine learning-based identification of colorectal advanced adenoma using clinical and laboratory data: a phase I exploratory study in accordance with updated World Endoscopy Organization guidelines for noninvasive colorectal cancer screening tests.

The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons.

A140 DELAYED BLEEDING POST-ENDOSCOPIC AMPULLECTOMY FOR AMPULLARY ADENOMAS: INCIDENCE, RISK FACTORS AND MANAGEMENT OF DELAYED BLEEDING

Abstract Background The duodenal tumors of major papilla account 10% of all peri-ampullary lesions, and the majority represent adenomas, carrying malignant potential through the well-known adenoma–carcinoma sequence ([i]). Historically, surgical resection was the standard of care, but it is associated with significant risk of complications (44.7%) ([ii]). Hence, endoscopic ampullectomy became the treatment modality for selected cases. Despite the significantly lower rate of adverse events, pancreatitis and bleeding occurs in up to 25% of patients ([iii]). The rate of bleeding may be even higher, depending on periampullary lesion size and type. Factors related to delayed bleeding are poorly understood. Aims The aim of our study was to determine predicting factors for delayed post-ampullectomy bleeding. Methods We conducted a single-center retrospective study over 13 years (2010-2023). All patients who underwent an endoscopic ampullectomy were analyzed. The primary endpoint was the incidence of delayed bleeding, which was defined as a post-procedural bleeding that necessitated either a blood transfusion, ICU admission or re-intervention. Secondary outcomes included risk factors for delayed bleeding, management, and other adverse events. Results 113 patients underwent endoscopic papillectomy [mean age 66.2 ± 12.2 years; male gender 51 (45.1%)]. Mean lesion size was 27.0 ± 14.3 mm and mean procedure duration was 62.8 ± 35.6 minutes. There were 24 cases of delayed bleeding (21.2%). Of these, 6 (25%) required repeat endoscopic intervention. The average length of hospital was longer in those experiencing a delayed bleed (8.6 ± 4.9 vs 4.8 ± 2.4 days, Pampersand:003C0.001). By univariable logistic regression, the odds of delayed bleeding were greater in those with hypertension (OR 3.8, 95%CI 1.4-10.3, P=0.008) or an INR ≥ 1.2 (OR 13.3, 95%CI 3.0-58.3, P=0.001). A multivariable logistic regression analysis revealed that INR≥ 1.2 predicted delayed bleeding, with an OR of 16.1 (95%CI 3.0-85.4, P=0.001). Other adverse events included perforation (n=7, 6.3%) and pancreatitis (n=19, 16.8%). There were no deaths. Conclusions Post-ampullectomy bleeding is a common adverse event in patients undergoing ampullectomy leading to more prolonged hospital stay. History of hypertension and elevated INR above 1.2 might be related to delayed post-ampullectomy bleeding. Additional strategies to reduce post-ampullectomy bleeding should be explored. Funding Agencies None

Advancements in endoscopic management of small-bowel polyps in Peutz-Jeghers syndrome and familial adenomatous polyposis.

Before the development of double-balloon enteroscopy (DBE), the standard management of small-bowel polyposis was surgical resection. This is an invasive procedure that could lead to short bowel syndrome. In the 21st century, several new enteroscopy techniques were distributed worldwide, including DBE, single-balloon enteroscopy, spiral enteroscopy, and motorized spiral enteroscopy. These devices enable the diagnoses and endoscopic interventions in the entire small bowel, even in patients with a history of laparotomy. In patients with Peutz-Jeghers syndrome (PJS), endoscopic ischemic polypectomy with clips or a detachable snare is the preferred method for managing pedunculated polyps because it is less likely to cause adverse events than conventional polypectomy. Although polyps in patients with PJS always recur, repeat endoscopic resection can reduce the total number and mean size of polyps in the long-term clinical course. Endoscopic reduction of small-bowel intussusception caused by PJS polyps can be successfully performed using DBE without surgery. A transparent hood is useful for securing a visual field during the treatment of small-bowel polyps, and minimal water exchange method is recommended to facilitate deep insertion. Familial adenomatous polyposis (FAP) is a genetic disorder that increases the risk of developing colorectal cancer. Because jejunal and ileal polyps in patients with FAP have the potential to develop into cancer via the adenoma-carcinoma sequence, periodical surveillance, and endoscopic resection are needed for them, not only polyps in the duodenum. In cases of multiple small-bowel polyps in patients with FAP, cold snare polypectomy without retrieval is an acceptable treatment option for polyps that are 10 mm or smaller in size. Additional good pieces of evidence are necessary to confirm these findings because this narrative review mostly includes retrospective observational studies from single center, case reports, and expert reviews.