Introduction

Inflammatory bowel disease (IBD) is associated with a higher risk of developing colorectal cancer, according to the inflammation-dysplasia-cancer (IDC) sequence from inflammation to colitis-associated colorectal cancer (CAC).

Aims & Methods

The objective of this study was to identify and generate a transcriptomic signature and score, related to the IDC sequence, that could ultimately classify dysplasia and cancer in IBD. This is a national cohort study conducted across 7 Belgian tertiary centres within the Belgian Inflammatory Bowel Disease Research and Development (BIRD) Group. We retrospectively evaluated IBD patients diagnosed with low- or high-grade dysplasia (LGD or HGD) and/or CAC between January 1, 1990, and December 31, 2016. An exploratory and a validation cohort of lesions were analysed. RNA-seq was analysed in 134 formalin-fixed paraffin-embedded samples. We followed an ordinal logistic regression (olm) method to screen for significant IDC sequence-associated genes and computed a transcriptomic signature score.

Results

Principal component analysis and unsupervised clustering on 1% of the most variable genes showed an overall good clustering between the 4 lesion groups (Normal Mucosa, Inflamed Mucosa, LGD and HGD, and CAC). A gene signature was identified on 27 genes that correlated with the lesion groups in the exploratory cohort. Among these 27 genes, 23 were downregulated and 4 were upregulated. Based on these 27-genes expression, we built and validated a transcriptomic signature score to classify dysplasia and CAC in IBD patients. The overall accuracy of the transcriptomic signature score was 85.71 % in the exploratory cohort and 90.91% in the validation cohort. The most weighted gene in this transcriptomic signature was the long non-coding regulatory RNA KCNQ1OT1, a gate keeper against genomic instability and transposon activation. We found a direct correlation in the expression of KCNQ1OT1 and retrotransposable elements (RTEs) across the lesion groups of IDC sequence.

Conclusion

We have identified a transcriptomic 27 gene signature associated with the IDC sequence and uncovered some of the pivotal genes and underlying mechanisms in the progression of the IDC sequence. The tissue-based transcriptomic score generated here helps the classification of the lesions of the IDC sequence in patients with IBD but should be further evaluated for its prognostic value in prospective independent cohorts. The most discriminant top gene in this signature, the non-coding RNA KCNQ1OT1, is consistent with the activation of RTEs that may be involved in the progression of the IDC sequence.

Introduction

Chronic inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are associated with an increased risk of various cancers, particularly colorectal cancer, but also other types, such as small intestine, biliary tract, or liver cancers. Additionally, certain extra-digestive cancers may also occur in patients with these conditions. These risks vary depending on the duration and severity of inflammation, as well as other factors such as family history or exposure to certain treatments. This work explores the diversity of cancers associated with IBD, their prevalence, and their clinical characteristics, highlighting the importance of considering these risks in the medical management of patients.

Aims & Methods

This is a retrospective and descriptive single-center study conducted within a hepatogastroenterology department, focusing on patients followed for inflammatory bowel diseases (IBD) who developed cancer. The study covers the period from 1990 to 2025.

Results

Out of a total of 1,795 patients followed for IBD (1,200 for Crohn's disease and 595 for ulcerative colitis), 2% (36 patients) developed cancer. The male-to-female sex ratio was 0.38, with a clear female predominance. Among the patients, 69.4% (25) had Crohn's disease, and 30.55% (11) had ulcerative colitis.
The most common location of Crohn's disease was colonic involvement (44%, 11 cases),the predominant phenotype was inflammatory (52%, 13 cases) ,for ulcerative colitis the most frequent location was left-sided colitis (54%, 6 cases) ,the median disease duration before the onset of cancer was 60 months.
Digestive cancers were the most commonly associated with IBD (38.8%, 14 cases), followed by breast cancer in women (30.5%, 11 cases), gynecological cancers (11.1%, 4 cases), prostate adenocarcinoma (5%, 2 cases), skin cancers (5%, 2 cases), and other cancers (5%, 2 cases).
Only 30.5% (11 patients) had risk factors (chronic smoking, family history of cancer, etc.).
Regarding treatment, 33% (12 patients) were on biologic therapy , 30.5% (11) were on azathioprin , 16.6% (6) were on therapeutic abstention , 8.3% (3) were on aminosalicylates, and 5.5% (2) were on corticosteroids.
Treatment was discontinued in 63.8% (23) of patients after the discovery of cancer, and 22% (8) experienced a flare-up which was successfully managed with corticosteroid therapy.
Eighty-three point three percent (83.3%, 30 patients) underwent surgical treatment alone or in combination with radiochemotherapy. Sixteen point six percent (16.6%, 6 patients) were at an advanced stage and had metastases, so they received palliative treatment.
Thirty-six percent (36%, 13 patients) had a good outcome, 30.5% (11) were lost to follow-up, and 2.7% (1) died.

Conclusion

The study shows a 2% cancer incidence in IBD patients, slightly higher than the general population's risk (0.3–0.5% annually), likely due to prolonged inflammation and disease duration. These findings highlight the need for enhanced cancer surveillance and preventive strategies, especially for patients with colonic involvement.

Introduction

The risk of synchronous colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) and high-grade dysplasia (HGD) is not known.

Aims & Methods

Study aim was to compare the risk of colorectal cancer at index colonoscopy in patients with HGD and IBD to patients with HGD without IBD. We also sought to evaluate the current management of visible HGD and invisible HGD, identified on random biopsies, in IBD. A retrospective cohort study was conducted. Through pathology database search, we identified all 1283 consecutive patients with an endoscopically resected colorectal HGD (biopsy or polypectomy), between 2010 and 2019 at the University of Montreal Hospital Center. We included patients aged 45-75 and excluded patients with polyposis syndromes, a history of CRC or index sigmoidoscopy. Files were reviewed for demographic data, index findings, IBD characteristics, and HGD management. Primary outcome was the risk of synchronous CRC at index colonoscopy in patients with HGD and IBD versus HGD and no IBD. Synchronous CRC was defined as CRC on index or CRC identified on surgery as the underlying lesion from which HGD was biopsied. Secondary outcomes were the proportion of visible and invisible HGD in IBD managed surgically. Continuous and categorical variables were compared using the Student t test, Pearson’s chi-squared test, or Mann-Whitney test. Multivariable logistic regression analysis was performed for the primary outcome.

Results

Overall, 982 patients with HGD without IBD (mean age 63 years; 55% male), and 37 patients with HGD and with IBD (mean age 59 years; 78% male; 62% ulcerative colitis; 38% Crohn’s disease; median time from IBD diagnosis to HGD is 17.0 years, mean 19.9 ± 13.4 years) were eligible based on inclusion and exclusion criteria above. In the HGD without IBD group, 294 patients out of 982 (29.9%) had synchronous CRC, with 260 CRCs found in the lesion where HGD was biopsied (26.5%), and 34 CRCs found in another location (3.5%). In the HGD with IBD group, 18 patients out of 37 (48.6%) had synchronous CRC, with 16 CRCs found in the lesion where HGD was biopsied (43.2%), and 2 CRCs found in another location (5.4%). Patients with HGD and IBD were more likely to have synchronous CRC compared to HGD and no IBD (odds ratio 2.22, 95%CI: 1.15-4.29). Out of 37 patients with IBD and HGD, 26 were managed surgically (70.3%), with 17 undergoing total colectomies, 4 right hemicolectomies, 4 transanal excisions, and 1 low anterior resection. Out of 37 patients with IBD and HGD, 8 had invisible HGD (21.6%) and all underwent total colectomy.

Conclusion

Patients with HGD and IBD are significantly more likely to have synchronous CRC compared to patients with HGD without IBD, with half of patients with HGD and IBD having synchronous CRC. Most patients with IBD and HGD are managed surgically, usually by total colectomy.

Disclosure

None

Introduction

While genetic susceptibility and environmental exposures are known contributors to the pathophysiology of Inflammatory Bowel Disease (IBD), their complex gene-environment interactions (GXE) remain elusive. This systematic review aims to summarize the current evidence of GXE in IBD.

Aims & Methods

PubMed, EMBASE, Web of Science and Scopus were systematically searched from inception through July 20, 2022 to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. All eligible studies were graded using the STREGA guideline.

Results

4,305 publications were identified and screened, resulting in 36 eligible studies. 17 studies reported statistically significant interactions.
NOD2-smoking interaction was most frequently investigated and showed variant-specific effects at rs2066847 regarding the risk of Crohn’s disease. Gene-smoking interactions were further identified in other IBD risk genes (ATG16L1, IL23R, and CALM3), detoxification genes (GSTP1 and ΗΜΟΧ1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, and BDNF), and the inflammatory cytokine (IL1B) through a candidate gene approach. Immunochip-wide interaction analyses yielded 64 smoking interacting variants.
Gene-diet interactions were observed across multiple nutritional measures, including fatty acid intake with CYP4F3 and FADS2, serum selenium with SEPHS1 and SEPSECS, potassium intake with IL21, alcohol consumption with IL12B, heme iron intake with FCGR2A and serum vitamin D with VDR.

Conclusion

Although previous studies have provided valuable insights into potential roles of GXE in the etiology of IBD, current evidence is sparse and inconclusive due to limited statistical power and lack of replication. Further studies, including genome wide environment interaction studies (GWEIS) and genotype-based nutrition/lifestyle clinical trials, are needed to unravel the missing heritability influenced by environmental exposures, and to construct personalized recommendations of lifestyle/dietary modification based on an individual genetic background.

Introduction

Dysbiosis of the microbiome is associated with inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of IBD. However, data are scarce and primarily limited to animal studies

Aims & Methods

We aimed to assess if stool microbiome characteristics are associated with disease severity, disease location, and inflammatory pathways using microbiome data obtained from the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s & Colitis Foundation for 926 CD and 491 UC patients. Characterization of stool shotgun metagenomics was conducted with MetaPhlAn2 and HUMAnN2 to determine abundance of taxa and functional pathways, respectively. ANOVA and linear regression analyses were conducted to associate bacterial composition and functional potential with the selected clinical and exploratory measures. Mucosal inflammation was assessed with mucosal transcriptome data.

Results

Most of the samples came from Caucasians and females, and approximately 70% patients were in remission. 295 of 727 patients with CD had disease location data and 83% of these patients had ileal involvement (Table 1). We observed distinct microbial profiles between patients with active disease versus inactive disease in both CD and UC. Specifically, oral commensals belonging to Veillonella, Klebsiella, Rothia, and Megasphaera were more abundant in patients with active disease in both CD and UC, while 21 genera including butyrate producing species belonging to Anaerostipes, Ruthenibacterium, Faecalibacterium and Roseburia were more abundant in patients with inactive disease in both CD and UC. We also noted differences in relative abundances of bacterial taxa by disease activity separately within UC and CD. In UC, the fecal microbial signatures with active disease were enriched with Escherichia, Haemophilus, and Anaerococcus, while Lactococcus, Proteobacteria_unclassified, Parasutterella, and Gemella were more abundant in patients with inactive disease. In CD, 9 unique genera were more abundant in patients with active disease, and 24 unique genera were more abundant in patients with inactive disease, consistent with the fact that CD manifests in both isolated disease locations (ileum or colon) or a combination of locations (ileocolonic) and UC is limited to the colon and the rectum. Indeed, 32 out of the 33 genera specific to CD, but not UC, were found to be associated with altered enrichment in ileal or ileocolonic CD compared to colonic CD, when stratifying by disease location.

Table 1 Population characteristics including disease activity (CD and UC) and CD disease location

Conclusion

Differences in microbiota by disease location suggest separate location-specific pathologies. Location-specific interactions between host intestinal gene expressions and microbiota, suggest key immune-mediated molecular pathways and relevant bacteria in intestinal tissue, which may guide drug development and precision medicine in IBD.

Disclosure

Christopher Morehouse, Ben Sparklin, Bret Sellman, Antonio DiGiandomenico, Vancheswaran Gopalakrishnan, Bastian Angermann, Ulf Gehrmann, Jessica Neisen, Emon Khan and Junmei Cairns are all employees of AstraZeneca.