IBD-associated Colorectal Cancer Research Articles

ITGB2 related to immune cell infiltration as a potential therapeutic target of inflammatory bowel disease using bioinformatics and functional research.

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition regarded as a major risk factor for colitis-associated cancer. However, the underlying mechanisms of IBD remain unclear. First, five GSE data sets available in GEO were used to perform 'batch correction' and Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs). Candidate molecules were identified using CytoHubba, and their diagnostic effectiveness was predicted. The CIBERSORT algorithm evaluated the immune cell infiltration in the intestinal epithelial tissues of patients with IBD and controls. Immune cell infiltration in the IBD and control groups was determined using the least absolute shrinkage selection operator algorithm and Cox regression analysis. Finally, a total of 51 DEGs were screened, and nine hub genes were identified using CytoHubba and Cytoscape. GSE87466 and GSE193677 were used as extra data set to validate the expression of the nine hub genes. CD4-naïve T cells, gamma-delta T cells, M1 macrophages and resting dendritic cells (DCs) are the main immune cell infiltrates in patients with IBD. Signal transducer and activator of transcription 1, CCR5 and integrin subunit beta 2 (ITGB2) were significantly upregulated in the IBD mouse model, and suppression of ITGB2 expression alleviated IBD inflammation in mice. Additionally, the expression of ITGB2 was upregulated in IBD-associated colorectal cancer (CRC). The silence of ITGB2 suppressed cell proliferation and tumour growth invitro and invivo. ITGB2 resting DCs may provide a therapeutic strategy for IBD, and ITGB2 may be a potential diagnostic marker for IBD-associated CRC.

Colorectal cancer in inflammatory bowel disease: a review of the role of gut microbiota and bacterial biofilms in disease pathogenesis.

The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.

Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review).

The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.

Colorectal cancer in inflammatory bowel diseases in St. Petersburg: results of an analytical study

Introduction. Ulcerative colitis (UC) and Crohn’s disease (CD) belong to the category of inflammatory bowel disease (IBD) and are one of the most pressing problems of gastroenterology worldwide, including due to the development of specific life-threatening complications. Chronic inflammation in the colon in IBD is the cause of the development of one of these complications - colorectal cancer, which requires disabling colectomies and is also one of the leading causes of death among IBD patients. In the Russian population of IBD patients the prevalence of dysplasia and cancer of the colon mucosa has not been previously studied in large epidemiological studies. The aim of the study was to assess the incidence of colorectal cancer in patients with IBD in St. Petersburg. Materials and methods. Within the framework of this publication, the results of three studies were compared: a single-center retrospective cohort study conducted on the basis of the city center of IBD in St. Petersburg (516 patients with IBD who admitted to this medical institution for the period 2020-2023); a multicenter epidemiological study aimed at assessing the clinical features of IBD among the population of St. Petersburg (1072 patients with IBD who admitted to 42 outpatient clinics and 6 city hospitals in 2018-2020); registry study based on the general statistical module of the regional IBD Register of St. Petersburg, operating on the basis of a regional fragment of the unified healthcare state information system (12,858 patients with IBD, data collection period: 2019-2022). Results. As a result of comparing data from three studies, the incidence of IBD-associated colorectal cancer in St. Petersburg was calculated, which was 15.7 cases per 10,000 patients with UC per year and 11.5 cases per 10,000 patients with CD per year. Compared to the population of St. Petersburg as a whole, the likelihood of developing colorectal cancer in patients with UC was 2.9 times higher, in patients with CD - 2.4 times higher. At the same time, in a single-center study, when assessing the prevalence of IBD-associated colorectal cancer, it was found that compared with other life-threatening complications of IBD, it was much less common: toxic dilatation of the intestine occurred 3 times more often, intestinal perforation occurred 20 times more often, decompensated bowel stricture occurred 21 times more often, and severe anemia requiring blood transfusion occurred 36 times more common. Also, as a result of a single-center study, it was found that for 1 case of IBD-associated dysplasia of the colon mucosa, there were 5 cases of sporadic dysplasia. Conclusion. The selection of the most effective therapy and systematic endoscopic examination of patients with IBD will significantly reduce the likelihood of developing colorectal cancer, and systematic observation of the patient with regular endoscopic monitoring of the colon with multifocal biopsy will allow timely detection of dysplasia of the colon mucosa in accordance with current clinical guidelines. It can be assumed that within the framework of cancer prevention measures in the first years of follow-up of a patient with IBD from the onset of the disease, it is advisable to give priority to the risk of developing not only IBD-associated dysplasia, but also sporadic dysplasia of the colon mucosa.

Advancements in Endoscopic Resection for Colitis-Associated Colorectal Neoplasia in Inflammatory Bowel Disease: Turning Visible into Resectable.

Patients suffering from inflammatory bowel disease (IBD) face a two to three-fold higher risk of developing colorectal cancer (CRC) compared to the general population. In recent years, significant progress has been made in comprehending the natural history of IBD-associated CRC (IBD-CRC) and refining its treatment strategies. The decreased incidence of IBD-CRC can be attributed to improved therapeutic management of inflammation, advancements in endoscopy, and early detection of precancerous lesions via surveillance programs. Advanced imaging technologies have made previously undetectable dysplasia visible in most cases, allowing for a much more precise and detailed examination of the mucosa. Additionally, new tools have facilitated the endoscopic resection (ER) of visible lesions in IBD. Particularly, the key to effectively manage colitis-associated colorectal neoplasia (CAN) is to first identify it and subsequently guarantee a complete ER in order to avoid surgery and opt for continuing surveillance. Advanced ER techniques for CAN include endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and hybrid ESD-EMR (h-ESD). This narrative review aims to consolidate the current literature on IBD-CRC, providing an overview of advanced techniques for ER of CAN in IBD, with a particular emphasis on the impact of ESD on the long-term outcomes of IBD patients.

Prognosis and molecular characteristics of IBD-associated colorectal cancer: Experience from a French tertiary-care center.

Little is known about the prognosis of colorectal cancer associated with inflammatory bowel disease (CRC-IBD) in a real-world cohort in France. We conducted a retrospective observational study including all patients presenting CRC-IBD in a French tertiary center. Among 6510 patients, the rate of CRC was 0.8% with a median delay of 19.5 years after IBD diagnosis (median age 46 years, ulcerative colitis 59%, initially localized tumor 69%). There was a previous exposure to immunosuppressants (IS) in 57% and anti-TNF in 29% of the cases. A RAS mutation was observed in only 13% of metastatic patients. OS of the whole cohort was 45 months. OS and PFS of synchronous metastatic patients was 20.4 months and 8.5 months respectively. Among the patients with localized tumor those previously exposed to IS had a better PFS (39 months vs 23 months; p=0.05) and OS (74vs 44 months; p=0.03). The IBD relapse rate was 4%. No unexpected chemotherapy side-effect was observed CONCLUSIONS: OS of CRC-IBD is poor in metastatic patients although IBD is not associated with under-exposure or increased toxicity to chemotherapy. Previous IS exposure may be associated with a better prognosis.

Exploring the glycolytic cross-talk genes between inflammatory bowel disease and colorectal cancer

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer (CRC). Glycolysis is involved in the development of both IBD and CRC. However, the mechanisms and outcomes of glycolysis shared between IBD and CRC remain unclear. This study aimed to explore the glycolytic cross-talk genes between IBD and CRC integrating bioinformatics and machine learning. With WGCNA, LASSO, COX, and SVM-RFE algorithms, P4HA1 and PMM2 were identified as glycolytic cross-talk genes. The independent risk signature of P4HA1 and PMM2 was constructed to predict the overall survival rate of patients with CRC. The risk signature correlated with clinical characteristics, prognosis, tumor microenvironment, immune checkpoint, mutants, cancer stemness, and chemotherapeutic drug sensitivity. CRC patients with high risk have increased microsatellite instability, tumor mutation burden. The nomogram integrating risk score, tumor stage, and age showed high accuracy for predicting overall survival rate. In addition, the diagnostic model for IBD based on P4HA1 and PMM2 showed excellent accuracy. Finally, immunohistochemistry results showed that P4HA1 and PMM2 were significantly upregulated in IBD and CRC. Our study reveals the presence of glycolytic cross-talk genes P4HA1 and PMM2 between IBD and CRC. This may prove to be beneficial in advancing research on the mechanism of development of IBD-associated CRC.

Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis.

Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.

Inflammation-Driven Colorectal Cancer Associated with Colitis: From Pathogenesis to Changing Therapy

Patients affected by inflammatory bowel disease (IBD) have a two-fold higher risk of developing colorectal cancer (CRC) than the general population. IBD-related CRC follows a different genetic and molecular pathogenic pathway than sporadic CRC and can be considered a complication of chronic intestinal inflammation. Since inflammation is recognised as an independent risk factor for neoplastic progression, clinicians strive to modulate and control disease, often using potent therapy agents to achieve mucosal healing and decrease the risk of colorectal cancer in IBD patients. Improved therapeutic control of inflammation, combined with endoscopic advances and early detection of pre-cancerous lesions through surveillance programs, explains the lower incidence rate of IBD-related CRC. In addition, current research is increasingly focused on translating emerging and advanced knowledge in microbiome and metagenomics into personalised, early, and non-invasive CRC screening tools that guide organ-sparing therapy in IBD patients. This review aims to summarise the existing literature on IBD-associated CRC, focusing on new insights into the alteration of the intestinal barrier and the interactions with the gut microbiome as the initial promoter. In addition, the role of OMIC techniques for precision medicine and the impact of the available IBD therapeutic armamentarium on the evolution to CRC will be discussed.

Effects of Medicinal Plants and Phytochemicals in Nrf2 Pathways during Inflammatory Bowel Diseases and Related Colorectal Cancer: A Comprehensive Review.

Inflammatory bowel diseases (IBDs) are related to nuclear factor erythroid 2-related factor 2 (Nrf2) dysregulation. In vitro and in vivo studies using phytocompounds as modulators of the Nrf2 signaling in IBD have already been published. However, no existing review emphasizes the whole scenario for the potential of plants and phytocompounds as regulators of Nrf2 in IBD models and colitis-associated colorectal carcinogenesis. For these reasons, this study aimed to build a review that could fill this void. The PubMed, EMBASE, COCHRANE, and Google Scholar databases were searched. The literature review showed that medicinal plants and phytochemicals regulated the Nrf2 on IBD and IBD-associated colorectal cancer by amplifying the expression of the Nrf2-mediated phase II detoxifying enzymes and diminishing NF-κB-related inflammation. These effects improve the bowel environment, mucosal barrier, colon, and crypt disruption, reduce ulceration and microbial translocation, and consequently, reduce the disease activity index (DAI). Moreover, the modulation of Nrf2 can regulate various genes involved in cellular redox, protein degradation, DNA repair, xenobiotic metabolism, and apoptosis, contributing to the prevention of colorectal cancer.

P132 Prognosis and molecular characteristics of IBD-associated colorectal cancer: experience from a French tertiary-care center

Abstract Background Little is known about the prognosis of colorectal cancer associated with inflammatory bowel disease (CRC-IBD) in a real-world cohort in France. Methods We conducted a retrospective observational study including all patients presenting CRC-IBD in a tertiary French center between 1990 and 2021. Clinical and molecular data were collected. We analyzed overall survival (OS), progression free survival (PFS) and factors associated with prognosis. Outcome probabilities were analyzed using the Kaplan-Meier method. Results Among 6510 patients, the incidence rate of CRC was 0.8% (N =49) with a median delay of 19.5 years after IBD diagnosis. The median age was 46 years, the main IBD was ulcerative colitis (59%), the primary tumor was rectal in 49% and localized at diagnosis in 69%. There was a previous exposure to immunosuppressants (IS) in 57% and anti-TNF in 29% of the cases. The most frequent mutation was TP53 (56%). A RAS mutation was observed in 37% of the whole population and 13% of metastatic patients. OS of the whole cohort was 45 months OS and PFS of synchronous metastatic patients was 20.4 months and 8.5 months respectively. Among the patients with localized tumor those previously exposed to IS had a better progression-free survival (39 months vs 23 months; p =0.05) and a better OS (74 vs 44 months; p =0.03). Only 2 patients (4%) experienced IBD relapse during follow-up despite IS and biologics discontinuation in all exposed patients. Chemotherapy exposure was 53% and 93% in the adjuvant and metastatic setting respectively. No unexpected side-effect was observed, the only reason for discontinuation was oxaliplatin-sensitive neuropathy. Conclusion Incidence of CRC is elevated in IBD patients with a poor OS in metastatic patients although IBD is not associated with under-exposure or increased toxicity to chemotherapy. Previous IS exposure may be associated with a better prognosis.

Inflammatory Bowel Disease and Colorectal Cancer

AbstractThe prevalence of inflammatory bowel disease (IBD) continues to rise with the increasing rates in the developing world and the improving longevity of IBD patients. A diagnosis of colonic IBD is associated with an increased risk of colorectal cancer (CRC) and this accounts for approximately 15% of the estimated mortality from IBD. CRC in IBD appears to be a pathologically distinct entity and progress is being made to understand the unique components of this process with a view to better predicting outcomes and potentially improving surveillance, treatments, and eventually modifying risk. In the interim, patients are entered into surveillance programs designed to identify at-risk patients early and improve outcomes. Dramatic evolution of technology in this area has changed the landscape of surveillance and dysplasia management over the last decade and promises to continue to do so. This review aims to provide a contemporary overview of IBD-associated CRC in terms of its epidemiology, pathogenesis, surveillance, and management.

Multi-unit pellet drug delivery system of Danggui Decoction extracts for chemoprevention of IBD-associated colorectal cancer in rats

Anti-inflammation has become pivotal in chemoprevention of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC). The chemopreventive effects of anti-inflammatory drugs currently used in IBD therapy are still not clear based on existing epidemiological studies. Therefore, novel chemopreventive candidates need to be investigated and natural products derived from food as well as complementary and alternative medicine have become attractive resources with advantages including multi-components and multi-targets. Danggui Decoction (DGD), composed of Angelicae Sinensis Radix, Zingiberis Recens Rhizoma and Jujubae Fructus, is a traditional Chinese medicinal formula for the treatment of IBD, and DGD supercritical fluid extracts (DGDSFE) as well as DGD polysaccharide extracts (DGDPE) are potential effective constituents for chemoprevention. This article constructed a multi-unit pellet drug delivery system (MUPDDS) containing two independent parts, DGDSFE colon-targeted pellets and DGDPE pellets, according to the different characteristics of extracts, by applying extrusion-spheronization and coating technology. The chemopreventive effect of this MUPDDS was evaluated in the rat model induced by 1,2-dimethylhydrazine and dextran sulfate sodium. The tumor incidence, tumor number and tumor volume were reduced after the administration of MUPDDS daily for 14 weeks, with serum levels of TNF-α, IL-1β and hepcidin decreased and levels of IFN-γ and IL-2 in splenocyte supernatant elevated, indicating anti-inflammation, iron metabolism regulation and immune regulation of DGDSFE and DGDPE in MUPDDS. Furthermore, the feasibility and advantage of MUPDDS in chemoprevention was displayed by compared with extracts, DGDSFE colon-targeted pellets or DGDPE pellets, providing an inspiring strategy to achieve better effect of traditional Chinese medicines in cancer prevention.

Risk factors for colorectal cancer in IBD patients

A characteristic feature of inflammatory bowel diseases (IBD) is an increased risk of neoplasia and colorectal cancer (CRC). The introduction of screening programs, as well as modern advances in therapy and endoscopic technologies, awareness of the risk factors of IBD-associated CRC will contribute to reducing the frequency of this dangerous complication of IBD. The presented review describes epidemiological data on the incidence of IBD-associated CRC, established risk factors for CRC, as well as modern methods of prevention, screening and early diagnosis. Literature search was conducted in PubMed and Google Scholar systems by keywords: inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, colorectal cancer, risk factors, screening, endoscopy, dysplasia.

Gut microbiota, inflammatory bowel disease and colorectal cancer.

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn’s disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.

Abstract 3801: Comprehensive characterization of the biology of inflammatory bowel disease-associated colorectal cancer using the GeoMx® Digital Spatial Profiler (DSP)

Abstract Inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) significantly increases the risk for development of colorectal cancer (CRC). However, the exact molecular mechanisms that underlie the transition from inflammation to cancer are not fully understood, and a systematic characterization of the immunopathogenesis of IBD-associated CRC is lacking. To address this issue, we will perform a comprehensive and spatial tissue analysis using the Cancer Transcriptome Atlas (CTA) on the NanoString GeoMx® Digital Spatial Profiler (DSP). The CTA panel is designed to profile the global immune response and all aspects of tumor microenvironment biology, including the 18-gene Tumor Inflammation Signature (TIS). For DSP analysis, a total of 20 FFPE samples (5 colon cancer patients, 5 UC patients, 5 CD patients, and 5 matched normal samples will be spatially profiled for up to 1,800 genes included on the CTA. Selection of regions of interest (ROI) will be guided by H&E staining and fluorescent markers (CD45, PanCK, Syto13), and profiling of tumor and TME regions will be achieved through segmenting by PanCK+/PanCK- followed by collection of indexed oligonucleotides and sequenced on NextSeq 550 Illumina instrument. NGS reads will be processed into digital counts, normalized and mapped back to each ROI, generating a map of transcript activity within each ROI. For all samples crypt and villus regions will be selected for a detailed spatial analysis. Subsequently, using the proprietary multiplex immunofluorescence (mIF) platform MultiOmyx™ we will characterize the protein immune cell landscape in IBD-associated CRC, using a custom immune panel applied to adjacent slides. With this study we hope to highlight genes and pathways involved in the transition from inflammation to cancer by combining large-scale spatial gene profiling by DSP CTA with a comprehensive spatial protein profiling by MultiOmyx. It is our hope that this will provide some much-needed understanding of the underlying mechanisms leading from an IBD disorder to the development of colon cancer. Citation Format: Anna Juncker-Jensen, Lakshmi Chandramohan. Comprehensive characterization of the biology of inflammatory bowel disease-associated colorectal cancer using the GeoMx® Digital Spatial Profiler (DSP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3801.

Abstract 5078: Metaproteomic analysis of IBD associated colorectal cancer

Abstract Inflammatory bowel disease (IBD) increases the risk of developing colorectal cancer by 60%. The composition of gut flora and its interaction with mucosal cells plays a key role in the development of IBD and colorectal cancer. However, the actual cause-effect relationship between dysbiosis of the gut microbiome and human IBD and associated colorectal cancer has not been well established. In the current study, we sought to characterize colon mucosa adherent microbiota using metaproteomics to understand the colon micro-environment and the host-microbiome interactions. Three groups of colon biopsies were included in our analysis: healthy controls, Non-progressors (IBD patients without dysplasia or cancer) and Progressors (IBD patients who have dysplasia or cancer). The biopsy samples were analyzed by LC MS/MS and the bacterial proteins were identified using the Human Microbiome Project (HMP) human gut microbiome database. The inferences of bacterial taxonomy, bacterial enzymes and Gene ontology (GO) pathways were processed through Unipept. Examining bacterial composition between different sample groups showed no statistically significant difference at the levels of phyla and classes. However, a significant reduction of Holdemanella biformis was observed when comparing Progressors vs Non-progressors. Holdemanella biformis has recently been proposed to be endogenous anti-tumourigenic bacterial strains. Decrease of this bacterial species in Progressors suggested that it may be a protective bacteria preventing the progression of IBD associated colorectal cancer. Analysis of Gene Ontology (GO) biological processes identified GO terms that were significantly different among the Progressor, Non-progressor and healthy groups. For example, the GO term ‘detoxification of arsenic containing substances’ was significantly underrepresented in the Progressor group compared to healthy and Non-progressor groups. Furthermore, several bacterial enzymes were significantly different between the three groups. In particular, oxidoreductases were significantly decreased in the Progressor group compared to healthy and Non-progressor groups. While the implications of these significantly enriched or depleted bacterial biological processes and bacterial enzymes in the neoplastic progression of IBD warrant further investigation, the results from our current study provide new insight into understanding how gut microbiota as a modulator of microenvironment may contribute to progression of IBD-associated colorectal cancer. Citation Format: Nobel Bhasin, Prerna Dabral, Victoria Poplaski, Lisa Lai, Hong-Yuan Tsai, Mary Bronner, Teresa Brentnall, John Valentine, Jordon March, Antone Opekun, Robert Britton, Pan Sheng, Ru Chen. Metaproteomic analysis of IBD associated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5078.

Genetic Profiling of Colorectal Carcinomas of Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.

BackgroundPatients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) run a 10-fold increased risk of developing colorectal cancer (CRC) compared to patients with IBD only. The aim of this study was to perform an extensive screen of known carcinogenic genomic alterations in patients with PSC-IBD, and to investigate whether such changes occur already in nondysplastic mucosa.MethodsArchival cancer tissue and nondysplastic mucosa from resection specimens of 19 patients with PSC-IBD-CRC were characterized, determining DNA copy-number variations, microsatellite instability (MSI), mutations on 48 cancer genes, and CpG island methylator phenotype (CIMP). Genetic profiles were compared with 2 published cohorts of IBD-associated CRC (IBD-CRC; n = 11) and sporadic CRC (s-CRC; n = 100).ResultsPatterns of chromosomal aberrations in PSC-IBD-CRC were similar to those observed in IBD-CRC and s-CRC, MSI occurred only once. Mutation frequencies were comparable between the groups, except for mutations in KRAS, which were less frequent in PSC-IBD-CRC (5%) versus IBD-CRC (38%) and s-CRC (31%; P = .034), and in APC, which were less frequent in PSC-IBD-CRC (5%) and IBD-CRC (0%) versus s-CRC (50%; P < .001). Cases of PSC-IBD-CRC were frequently CIMP positive (44%), at similar levels to cases of s-CRC (34%; P = .574) but less frequent than in cases with IBD-CRC (90%; P = .037). Similar copy number aberrations and mutations were present in matched cancers and adjacent mucosa in 5/15 and 7/11 patients, respectively.ConclusionsThe excess risk of CRC in patients with PSC-IBD was not explained by copy number aberrations, mutations, MSI, nor CIMP status, in cancer tissue, nor in adjacent mucosa. These findings set the stage for further exome-wide and epigenetic studies.

Ulcerative Colitis-Induced Colorectal Carcinoma: A Deleterious Concatenation.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal ailment that encompasses Crohn's disease (CD) and ulcerative colitis (UC). UC is an idiopathic, chronic inflammatory condition of the colonic mucosa that begins in the rectum and progresses proximally in a continuous way over a portion of the entire colon. Chronic inflammation is linked to cancer, and IBD-related chronic colonic inflammation raises the risk of colorectal cancer. Chronic inflammation has been linked to cancer, and chronic colonic inflammation caused by IBD increases the risk of colorectal cancer (CRC). When CRC arises in people with IBD, unlike sporadic CRC, the lesions are difficult to identify due to mucosal alterations produced by inflammation. The total prevalence of IBD-associated CRC is increasing due to the rapidly increasing frequency of IBD. Screening and surveillance colonoscopy in IBD patients is considered to allow for the early diagnosis of dysplasia and cancer, improving the prognosis of IBD-related CRC by giving patients proactive therapy. This article has reviewed literature pertaining to the mechanisms related to CRC development in UC and its clinical and therapeutic implications.

Outcomes of IBD-associated colorectal cancer and implications in early-onset colorectal cancer.

22 Background: Inflammatory bowel disease (IBD) increases the risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) mortality is on the rise. It has been postulated that CA-CRC may be contributing to the increasing prevalence of early-onset CRC (EOCRC) but supportive studies are currently lacking. Molecular and clinical differences between CA-CRC and sporadic-CRC (S-CRC) have been reported, however outcomes for CA-CRC remains unclear. Signet ring cell carcinoma (SRC) is a rare subtype of CRC which is seen at higher frequencies, along with mucinous histology, in both CA-CRC and EOCRC. In this study, we validate the association of SRC and mucinous (SRC/M) histology with CA-CRC and EOCRC, and utilize it to estimate the amount of EOCRC attributable to undiagnosed or subclinical IBD. Methods: A retrospective study was conducted using three independent mCRC patient datasets from MDACC. The mATTACC discovery cohort consisted of 32 IBD- and 425 S-mCRC patients enrolled in a prospective biomarker trial. Validation of tumor histology was completed with a tumor registry (n=1696), excluding the MSI-High samples, and a real-world evidence (RWE) cohort from MDACC containing 269 CA-mCRC and 29,596 S-mCRC patients, was used as our validation cohort. Results: In the mATTACC cohort SRC/M histology was found in 37.5% of CA-mCRC and 11.7% of S-mCRC, showing a strong association between SRC/M and CA-mCRC (OR = 4.54, 95% CI: 2.19-9.43). The RWE cohort confirmed the correlation of SRC/M with CA-mCRC (28.6%) relative to S-mCRC (11.4%) patients (OR = 3.13, 95%CI: 2.39-4.09). An association was found between SRC/M and EOCRC (OR = 1.35; 95% CI: 1.24-1.47). By comparing the prevalence of SRC/M in EOCRC and late-onset CRC and correcting by the proportion of CA-CRC cases with SRC/M histology, we estimate that between 8.28% to 10.15% of EOCRC may attributable to undiagnosed/subclinical IBD. Using the RWE cohort, median overall survival was determined to be lower for CA-mCRC (31m) relative to S-mCRC (39m; p=0.007), yielding a HR of 1.26 (95% CI: 1.06-1.48). CA-mCRC patients with EOCRC (25m) were also found to have significantly worse outcomes than S-mCRC patients (40m) with EOCRC (p=0.0005; HR = 1.61, 95%CI: 1.23-2.11). Within CA-mCRC, patients with SRC or SRC/M histology (21m) had decreased OS compared to mucinous histology (51m), indicating the poor prognosis of SRC in CA-mCRC (p=0.028; HR=0.53, 95% CI: 0.3-0.94). Conclusions: Tumor biology consistent with CA-CRC, including SRC/M histology, may be present in 8.3% – 10.2% of patients with EOCRC without a clinical diagnosis of IBD, and harbors worse outcomes. Although other confounding biology may be underlying this association, recognition of undiagnosed IBD in CRC patients, especially those with metastatic disease, is important as it may impact prognosis and treatment strategies for this high-risk patient population.