Inflammatory Bowel Disease-associated Colorectal Cancer Research Articles

Inflammatory bowel disease-associated colorectal cancer negatively affects surgery outcomes and health care costs

BackgroundInflammatory bowel disease may affect the pathogenesis and clinicopathologic course of colorectal cancer. We sought to characterize the impact of inflammatory bowel disease on outcomes after colectomy and/or proctectomy for a malignant indication. MethodsPatients diagnosed with colorectal cancer as well as a pre-existing comorbid diagnosis of Crohn's disease or ulcerative colitis between 2018 and 2021 were identified from Medicare claims data. The postoperative textbook outcome was defined as the absence of complications, as well as no extended hospital stay, 90-day readmission, or mortality. Postdischarge disposition and expenditures were also examined. ResultsAmong 191,684 patients with colorectal cancer, 4,770 (2.5%) had a pre-existing diagnosis of inflammatory bowel disease. Patients with inflammatory bowel disease-associated colorectal cancer were less likely to undergo surgical resection (no inflammatory bowel disease: 47.6% vs inflammatory bowel disease: 42.1%; P < .001). Among patients who did undergo colorectal surgery, individuals with inflammatory bowel disease were less likely to achieve a textbook outcome (odds ratio 0.64 [95% confidence interval 0.58–0.70]). In particular, patients with inflammatory bowel disease had higher odds of postoperative complications (odds ratio 1.24 [1.12–1.38]), extended hospital stay (odds ratio 1.41 [1.27–1.58]), and readmission within 90 days (odds ratio 1.56 [1.42–1.72]) (all P < .05). Patients with inflammatory bowel disease-associated colorectal cancer were less likely to be discharged to their home under independent care (odds ratio 0.77 [0.68–0.87]) and had 12.2% higher expenditures, which correlated with whether the patient had a postoperative textbook outcome. ConclusionOne in 40 patients with colorectal cancer had concomitant inflammatory bowel disease. Inflammatory bowel disease was associated with a lower probability of achieving ideal postoperative outcomes, higher postdischarge expenditure, as well as worse long-term survival after colorectal cancer resection.

N08 Awareness of Inflammatory Bowel Disease-associated Colorectal Cancer risk and its management in patients with Inflammatory Bowel Disease: a systematic review

Abstract Background Inflammatory bowel disease (IBD) increases the risk of colorectal cancer (CRC). Although literature exists on patients’ general IBD knowledge, little is known about IBD patients’ awareness of CRC risk. This systematic review aimed to explore the literature on IBD patients’ knowledge, attitudes, and awareness of CRC risk and its management. Methods Medline, EMBASE, and PubMed databases were searched from inception to November 2023. All study designs and publication types were included. Non-English articles and those assessing general IBD knowledge were excluded. Cochrane’s ‘checklist of items to consider in data extraction’ was adapted for data extraction and the appraisal tool for cross-sectional studies (AXIS) was used to appraise the quality of included studies. All data relevant to the review question were extracted from the included studies and were thematically analysed for main themes. Results Twenty-three studies (17 full papers and 6 conference abstracts), including 4674 participants (2481 Ulcerative Colitis, 53.5% females) were included (PRISMA diagram Figure 1). The quality of included studies ranged from moderate to low. Overall, 18 studies reported CRC risk knowledge, 3 studies reported patients’ knowledge of CRC symptoms and risk factors, 7 reported attitudes towards cancer screening and 8 reported patient knowledge or attitude towards colectomy for dysplasia. The review found that IBD patients were moderately aware of the CRC risk, poorly aware of the symptoms and risk factors for CRC, and moderately feared this complication of IBD. Most overestimated their own risk of CRC and wanted more discussion with health professionals. Although the role of colonoscopy in cancer screening and diagnosis was well known, patients expressed mixed attitudes towards it due to the unpleasantness of bowel preparation, discomfort, or fear of colonoscopy complications. Low awareness of screening initiation time and varied willingness to undergo colectomy for dysplasia, irrespective of the extent of risk, was reported. Surgery was reported to be a last resort. Conclusion Limited literature exists on IBD patients’ awareness of CRC risk and its management to confidently infer the level of awareness and extent of educational needs of IBD patients. More research is needed to establish patients’ understanding of CRC risk and to optimise management.

Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational and Transformational Risks Posed by Exogenous Free Hemoglobin Alpha Chain, A By-Product of Extravasated Erythrocyte Macrophage Erythrophagocytosis.

Colonic inflammatory bowel disease (IBD) encompasses ulcerative colitis (UC) and Crohn's colitis (CC). Patients with IBD are at increased risk for colitis-associated colorectal cancer (CACRC) compared to the general population. CACRC is preceded by IBD, characterized by highly heterogenous, pharmacologically incurable, pertinacious, worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the duration and severity of inflammation, which is influenced by the exogenous free hemoglobin alpha chain (HbαC), a byproduct of infiltrating immune cells; extravasated erythrocytes; and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS), which is exacerbated by decreased tissue antioxidant defenses. Mitigation of the Fenton Reaction via pharmaceutical therapy would attenuate ROS, promote apoptosis and DNAD repair, and subsequently prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin's clearance rate from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Further, deferoxamine's hydrophilic structure limits its ability to cross cell membranes. Finally, the effectiveness of flavonoids, natural herb antioxidants, is associated with the high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. The molecular immunopathogenesis pathways of CACRC herein reviewed are broadly still not well understood. Therefore, this timely review outlines the molecular and immunological basis of disease pathogenesis and pharmaceutical intervention as a protective measure for CACRC.

QuPath Algorithm Accurately Identifies MLH1-Deficient Inflammatory Bowel Disease-Associated Colorectal Cancers in a Tissue Microarray.

Current methods for analysing immunohistochemistry are labour-intensive and often confounded by inter-observer variability. Analysis is time consuming when identifying small clinically important cohorts within larger samples. This study trained QuPath, an open-source image analysis program, to accurately identify MLH1-deficient inflammatory bowel disease-associated colorectal cancers (IBD-CRC) from a tissue microarray containing normal colon and IBD-CRC. The tissue microarray (n = 162 cores) was immunostained for MLH1, digitalised, and imported into QuPath. A small sample (n = 14) was used to train QuPath to detect positive versus no MLH1 and tissue histology (normal epithelium, tumour, immune infiltrates, stroma). This algorithm was applied to the tissue microarray and correctly identified tissue histology and MLH1 expression in the majority of valid cases (73/99, 73.74%), incorrectly identified MLH1 status in one case (1.01%), and flagged 25/99 (25.25%) cases for manual review. Qualitative review found five reasons for flagged cores: small quantity of tissue, diverse/atypical morphology, excessive inflammatory/immune infiltrations, normal mucosa, or weak/patchy immunostaining. Of classified cores (n = 74), QuPath was 100% (95% CI 80.49, 100) sensitive and 98.25% (95% CI 90.61, 99.96) specific for identifying MLH1-deficient IBD-CRC; κ = 0.963 (95% CI 0.890, 1.036) (p < 0.001). This process could be efficiently automated in diagnostic laboratories to examine all colonic tissue and tumours for MLH1 expression.

P127 Inflammatory Bowel Disease-associated colorectal cancers: retrospective cohort study from a tertiary centre surveillance programme over 10 years

Abstract Background Patients with IBD have increased risk for developing colorectal cancer (CRC), with poorer survival, compared to those without IBD. Despite surveillance colonoscopy, IBD post-colonoscopy CRC (PCCRC) rates are unacceptably high at 28-45%. We define surveillance colonoscopy quality, IBD-dysplasia and IBD-CRC prevalence, IBD-CRC characteristics, and IBD PCCRC rates at a tertiary IBD centre. Methods The GI Reporting Tool (Unisoft Medical Systems) was searched for IBD surveillance colonoscopy reports from April 2008–December 2018. Electronic medical records were reviewed. IBD phenotype and diagnosis date was confirmed on the Lothian IBD Registry. Follow-up was until September 2022. Results 1892 colonoscopies from 1262 patients were included. Median follow-up was 7.1 (4.4, 9.5) years. 885/1262 (70.1%) had UC, 344/1262 (27.3%) had Crohn’s, and 33/1262 (2.6%) had IBD-U. Median disease duration at colonoscopy was 16.8 (11, 24.6) years. 1825/1892 (96.5%) colonoscopies achieved caecal intubation, 1735/1840 (94.3%) adhered to biopsy guidelines and 704/1892 (37%) used chromoendoscopy. Histological inflammation was identified in 873/1823 (47.9%) cases; 57.2% in the right colon. Bowel preparation was poor in 194/1892 (10.3%) procedures and the most documented reason for not performing chromoendoscopy. Poor bowel preparation was associated with 23/60 (38.3%) poorly tolerated and 29/52 (55.8%) incomplete colonoscopies. Moviprep was superior to Picolax (p&amp;lt;0.001). GI physicians were more likely to use chromoendoscopy (p&amp;lt;0.001), biopsy per guideline (p&amp;lt;0.001), and identify dysplasia (p=0.012) compared to surgical colleagues. Dysplasia was identified in 145/1892 (7.7%) colonoscopies: 84/1892 (4.4%) sporadic, 22/1892 (1.2%) IBD-associated, and 39/1892 (2.1%) unspecified. IBD-CRC is rare, at 0.8 cases per 1000 patient years. Within the study period, 20/1262 (1.6%) patients had CRC diagnosed. 17/20 (85%) had UC and 3/20 (15%) had Crohn’s. 15/17 (88%) UC patients had E3 disease. 11/20 (55%) presented with lymph node or distant metastasis. 8/20 (40%) tumours had mucinous differentiation; only 1/15 (6.7%) was well differentiated. IBD-CRC patients had longer disease duration (28.3 (19.7, 37.8) years) compared to patients without CRC (22.25 (16.42, 29.85) years) at follow-up (p=0.028). The 3-year PCCRC rate was 15%. Conclusion IBD-CRC is rare however IBD PCCRC rates are unacceptably high. While this may reflect disease biology, a new approach to IBD surveillance is urgently needed. Interventions could include dedicated IBD surveillance lists, patient education around bowel preparation, and pre-screening for inflammation (e.g. faecal calprotectin). Cancer registry database linkage is now essential for us to identify IBD-CRC cases not identified by surveillance.

Inflammatory Bowel Disease-Associated Colorectal Cancer Epidemiology and Outcomes: An English Population-Based Study.

Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.

Effect of Comorbidities on Inflammatory Bowel Disease-Related Colorectal Cancer: A Nationwide Inpatient Review.

Introduction The risk of inflammatory bowel disease-associated colorectal cancer (IBD-CRC) is known to increase with primary sclerosing cholangitis (PSC) and a family history of CRC. However, the impact of comorbidities such as liver disease, obesity, diabetes, chronic lung, heart, and renal disease, and psychiatric illness on the risk of IBD-CRC remains unclear. We evaluated the effect of these comorbidities on the risk of IBD-CRC.MethodsA retrospective review from 2009 to 2014 was conducted using the National Inpatient Sample data for adults 18 years and older. Patients with IBD (360,892), of whom 2,831 had CRC were identified using the International Classification of Diseases, Ninth Revision codes (ICD-9). Data on comorbidities were also obtained. Adjusted odds ratios (aOR) and confidence intervals (CI) were computed via logistic regression to evaluate the effect of comorbidities on the risk of IBD-CRC; the p-value was set at <0.05.ResultsThe mean age of IBD patients in this study was 52.36±0.03. A majority of the patients with IBD-CRC were white and were significantly older compared to those without cancer (60 vs 52 years, p<0.05). The risk of colon cancer in IBD was increased by having a non-cholestatic liver disease (aOR 1.51, CI 1.23-1.86, p<0.01). Also, patients younger than 50 years with liver disease were at an increased risk of IBD-associated colon cancer in comparison to older patients (aOR 1.83 vs 1.34, p<0.05). Notably, diabetes, chronic pulmonary disease, renal failure, psychiatric illnesses, and rheumatoid diseases, were inversely associated with the risk of IBD-CRC (p<0.05). After stratifying by IBD subtypes, non-cholestatic liver disease was still independently associated with a higher risk for colon cancer in patients with ulcerative colitis or Crohn's disease (ulcerative colitis: aOR 1.43, CI 1.08-1.89; Crohn's disease: aOR 1.46, CI 1.10-2.00).ConclusionsPatients with IBD who have non-cholestatic liver disease might have a higher risk for colon cancer, even at a younger age. These patients may require close colon cancer surveillance.

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&amp;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.

Survival Outcomes and Clinicopathological Features in Inflammatory Bowel Disease-associated Colorectal Cancer: A Systematic Review and Meta-analysis.

The aim of our study was to conduct a systematic review and meta-analysis comparing the survival outcomes of IBD-associated and non-IBD-associated CRC. Investigations comparing the prognosis in CRC patients with and without IBD have yielded conflicting results. PubMed/MEDLINE, Embase, Web of Science, Cochrane Library were searched for studies evaluating the prognostic outcomes between CRC patients with IBD and those without IBD. Estimates of survival-related outcomes and clinicopathological features in IBD-CRC and non-IBD CRC were pooled through random-effects or fix-effects models. The study is registered with PROSPERO, CRD42021261513. Of 12,768 records identified, twenty-five studies with 8034 IBD-CRC and 810,526 non-IBD CRC patients were included in the analysis. IBD-CRC patients have a significant worse overall survival (OS) with the hazard ratio (HR) of 1.33 [95% confidence interval (CI): 1.20-1.47] than those without IBD. Pooled estimates of cancer-specific survival demonstrated that IBD-CRC patients had a poorer cancer-specific survival than those without IBD with fixed-effect model (HR, 2.17; 95% CI: 1.68-2.78; P < 0.0001). Moreover, ulcerative colitis-associated CRC patients have favorable OS than Crohn's disease-associated CRC (HR 0.79,95% CI: 0.72-0.87). Compared to non-IBD-CRC, patients with IBD-associated CRC are characterized by an increased rate of poor differentiation (OR 2.02, 95% CI: 1.57-2.61), mucinous or signet ring cell carcinoma (OR 2.43, 95% CI: 1.34-4.42), synchronous tumors (OR 3.18, 95% CI: 2.26-4.47), right-sided CRC (OR 1.62, 95%CI: 1.05-2.05), male patients (OR 1.10, 95% CI: 1.05-1.16), and a reduced rate of R0 resections (OR 0.60, 95% CI: 0.44-0.82). IBD-CRC patients have a significant worse OS than patients with non-IBD CRC, which may be attributed to more aggressive histological characteristics and a lower rate of R0 resections at the primary tumor site. Optimized therapeutic standards and tailored follow-up strategies might improve the prognosis of IBD-CRC patients.

MicroRNA expression in inflammatory bowel disease-associated colorectal cancer.

MicroRNAs (miRNAs) are non-coding RNA molecules composed of 19–25 nucleotides that regulate gene expression and play a central role in the regulation of several immune-mediated disorders, including inflammatory bowel diseases (IBD). IBD, represented by ulcerative colitis and Crohn’s disease, is characterized by chronic intestinal inflammation associated with an increased risk of colorectal cancer (CRC). CRC is one of the most prevalent tumors in the world, and its main risk factors are obesity, physical inactivity, smoking, alcoholism, advanced age, and some eating habits, in addition to chronic intestinal inflammatory processes and the use of immunosuppressants administered to IBD patients. Recent studies have identified miRNAs associated with an increased risk of developing CRC in this population. The identification of miRNAs involved in this tumorigenic process could be useful to stratify cancer risk development for patients with IBD and to monitor and assess prognosis. Thus, the present review aimed to summarize the role of miRNAs as biomarkers for the diagnosis and prognosis of IBD-associated CRC. In the future, therapies based on miRNA modulation could be used both in clinical practice to achieve remission of the disease and restore the quality of life for patients with IBD, and to identify the patients with IBD at high risk for tumor development.

Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational Risks from Mechanisms to Medicines.

The cumulative impact of chronic inflammation in patients with inflammatory bowel diseases predisposes to the development of inflammatory bowel disease-associated colorectal cancer [IBD-CRC]. Inflammation can induce mutagenesis, and the relapsing–remitting nature of this inflammation, together with epithelial regeneration, may exert selective pressure accelerating carcinogenesis. The molecular pathogenesis of IBD-CRC, termed the ‘inflammation–dysplasia–carcinoma’ sequence, is well described. However, the immunopathogenesis of IBD-CRC is less well understood. The impact of novel immunosuppressive therapies, which aim to achieve deep remission, is mostly unknown. Therefore, this timely review summarizes the clinical context of IBD-CRC, outlines the molecular and immunological basis of disease pathogenesis, and considers the impact of novel biological therapies.

Temporal trend in inpatient mortality in inflammatory bowel disease-associated colorectal cancer vs non-inflammatory colorectal cancer: a nationwide retrospective study

Early detection and advancement in therapy have successfully achieved a steady decrease in colorectal cancer (CRC) mortality over the last two decades. On the other hand, studies investigating mortality trends in inflammatory bowel disease-associated CRC (IBD-CRC) are scarce and inconclusive. We conducted a retrospective analysis aiming to identify differences between inpatient mortality trends in IBD-CRC vs non-IBD-CRC and possible contributing factors. The National Inpatient Sample (NIS) database from 2006-2014 was queried to identify all patients admitted with a diagnosis of CRC. The main outcome was the prevalence and trend of mortality among IBD-CRC and non-IBD-CRC. The secondary outcome was the evaluation of predictors of inpatient mortality. A total of 1,190,759 weighted cases with the admission diagnosis of CRC were included in the study. Of which 10,997 (0.9%) had a co-diagnosis of IBD. The population with non-IBD-CRC had a statistically significant downward temporal trend in mortality (p < 0.001), while patients with IBD-CRC did not have any statistically significant temporal trend in inpatient mortality (p = 0.067). After subgroup analysis, patients with Crohn's disease-CRC had an upward temporal trend in mortality (p = 0.183) compared to patients with ulcerative colitis-CRC with a downward trend in mortality (p = 0.001). Sepsis resulted to be a stronger predictor of mortality for CD-CRC, while VTE for UC-CRC. Multiples strategies established to prevent morbidity and mortality in CRC have been fruitful in non-IBD-CRC population, but have not been enough for IBD-CRC population to cause the same effect. Further strategies are needed to achieve a reduction in IBD-CRC mortality trend.

S0828 Temporal Trend in Inpatient Mortality in Inflammatory Bowel Disease-Associated Colorectal Cancer vs Non-Inflammatory Colorectal Cancer: Insights From the National Inpatient Sample Database

S0828 Temporal Trend in Inpatient Mortality in Inflammatory Bowel Disease-Associated Colorectal Cancer vs Non-Inflammatory Colorectal Cancer: Insights From the National Inpatient Sample Database

Genomic and molecular alterations in human inflammatory bowel disease-associated colorectal cancer.

Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFβ pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.

P036 A novel p53-mediated mouse model of inflammatory bowel disease-associated colorectal cancer

Abstract Background Current mouse models of colitis-associated cancer often utilise a combination of APC mutation, Dextran sulphate sodium (DSS) and azoxymethane administration. However, only 13% of human inflammatory bowel disease (IBD)-associated cancers is associated with an APC mutation1. Instead, they are frequently associated with mutation of p53 (occurring in 63% of human cancers1). Whilst some models of IBD-associated cancer using either global p53 loss or mutant p53 have been described, we felt that a more pathophysiologically relevant model would be represented using p53 loss solely in the colonic epithelium. Methods Colonic epithelial p53 floxing in Vil-CreERT2p53fl/fl mice was achieved through intraperitoneal injection of 120 and 80 mg/kg tamoxifen on two consecutive days. After 16 days, mice were started on a chronic DSS treatment protocol. Chronic DSS-induced colitis involved three 5-day cycles of low-dose DSS (1.5% initially and subsequently 1% for the remaining two cycles), interspersed with normal drinking water for 2 weeks to facilitate recovery. After three cycles of DSS, mice were aged to 164 days. Results At 164 days post induction of DSS, 100% of mice had developed adenomata with low-grade dysplasia (n = 4). Adenomata in 50% of these mice (n = 2) also had features of high-grade dysplasia. There were between one and three adenomata in each animal. No features of invasive adenocarcinoma were demonstrated. There was partial β-catenin nuclear localisation in these tumours. Background chronic colitis was evident, even though the experiment ended over 3 months after the DSS treatment finished. Conclusion To the best our knowledge, this is the first mouse model of colitis-associated cancer using p53 loss in the colonic epithelium together with chronic colitis induction using DSS. The experiment ended over 3 months after the DSS treatment finished, showing that the resultant chronic colitis can persist long after the initial insult is given. The fact that β-catenin is partially, but not fully nuclear localised suggests an alternative pathway to tumour formation in this p53fl/fl model, and may therefore be more pathophysiologically relevant to human IBD-associated colorectal cancers. Further work is now being carried out to both validate and further evaluate this novel mouse model, including assessment of stem cell dynamics in response to colitis in the context of p53 loss. Reference

Similarities and differences in clinical and pathologic features of inflammatory bowel disease-associated colorectal cancer in China and Canada.

Background:Colorectal cancer (CRC) has become one of the major life-threatening complications in patients with inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). This study aimed to explore the clinical-pathologic similarities and differences in the IBD-associated CRC (IBD-CRC) between patients in China and Canada.Methods:Data of 78 patients with IBD-CRC retrospectively retrieved from two representative medical institutions in Beijing (China) and Calgary (Canada) over the same past 13 years, including 25 (22 UC-associated and three CD-associated) from Beijing group and 53 (32 UC-associated and 21 CD-associated) from Calgary group, were compared with regards to their clinical and pathologic characteristics.Results:Several known features of IBD-CRC were seen in both groups, including long duration and large extent of colitis, active inflammation background, multifocal lesions, and advanced tumor-node-metastasis stage. Beijing group showed a significantly higher percentage of UC (88.0% vs. 60.4%, P = 0.018), younger age at diagnosis of CRC (48.6 ± 12.8 years vs. 61.6 ± 14.7 years, P < 0.001), lower ratio of mucinous adenocarcinoma (7.1% vs. 42.4%, P = 0.001) compared with Calgary group. None of the Beijing group had concurrent primary sclerosing cholangitis, while 5.7% of Calgary group did. Surveillance colonoscopy favored the detection rate of precancerous lesions (41.4% vs.17.0%, P = 0.002).Conclusions:As compared with patients from the Calgary group, the IBD-CRC patients in Beijing group were younger, less CD-associated and had less mucinous features, otherwise they were similar in many common features.

Mutational Analysis Identifies Therapeutic Biomarkers in Inflammatory Bowel Disease-Associated Colorectal Cancers.

Purpose: Inflammatory bowel disease-associated colorectal cancers (IBD-CRC) are associated with a higher mortality than sporadic colorectal cancers. The poorly defined molecular pathogenesis of IBD-CRCs limits development of effective prevention, detection, and treatment strategies. We aimed to identify biomarkers using whole-exome sequencing of IBD-CRCs to guide individualized management.Experimental Design: Whole-exome sequencing was performed on 34 formalin-fixed paraffin-embedded primary IBD-CRCs and 31 matched normal lymph nodes. Computational methods were used to identify somatic point mutations, small insertions and deletions, mutational signatures, and somatic copy number alterations. Mismatch repair status was examined.Results: Hypermutation was observed in 27% of IBD-CRCs. All hypermutated cancers were from the proximal colon; all but one of the cancers with hypermutation had defective mismatch repair or somatic mutations in the proofreading domain of DNA POLE Hypermutated IBD-CRCs had increased numbers of predicted neo-epitopes, which could be exploited using immunotherapy. We identified six distinct mutation signatures in IBD-CRCs, three of which corresponded to known mechanisms of mutagenesis. Driver genes were also identified.Conclusions: IBD-CRCs should be evaluated for hypermutation and defective mismatch repair to identify patients with a higher neo-epitope load who may benefit from immunotherapies. Prospective trials are required to determine whether IHC to detect loss of MLH1 expression in dysplastic colonic tissue could identify patients at increased risk of developing IBD-CRC. We identified mutations in genes in IBD-CRCs with hypermutation that might be targeted therapeutically. These approaches would complement and individualize surveillance and treatment programs. Clin Cancer Res; 24(20); 5133-42. ©2018 AACR.

Associations between single-nucleotide polymorphisms and inflammatory bowel disease-associated colorectal cancers in inflammatory bowel disease patients: a meta-analysis.

To assess the correlation between single-nucleotide polymorphisms (SNPs) and inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) in IBD patients. A systematic search of PubMed, EmBase, and Cochrane databases was performed. Five genetic models (allelic, dominant, recessive, heterozygous and homozygous models) were used to analyze the associations, and trial sequential analysis was used to analyze the robustness of the results. We collected and analyzed the results of seven trials including a total of 2287 patients in our meta-analysis. A total of 8 SNPs were tested in IBD patients. For rs1800629 of TNF-α, the allelic model showed that polymorphism at this locus significantly increased the risk of IBD-associated CRC in IBD patients (OR 4.45, 95% CI 3.18-6.21, P<0.001). The results also showed a significant association between rs1800629 and an IBD-associated CRC population (heterozygous model: OR 4.335, 95% CI 2.329-8.069, P<0.001; homozygous model: OR 11.5, 95% CI 2.498-52.592, P=0.002; dominant model: OR 4.986, 95% CI 2.754-9.026, P<0.001; recessive model: OR 7.208, 95% CI 1.588-32.72, P=0.01). Other studies have found that mutation of rs1143627 of IL1B (allelic model: OR 2.97; 95% CI 1.74-5.05, P<0.001) and rs1050152 of OCTN1 (allelic model: OR 1.637, 95% CI 1.078-2.485, P=0.021) increased the proportion of IBD-associated CRC in the population. Moreover, there were significant associations between IBD-associated CRC and ITLN rs2274910, gene desert rs1551398 and rs4871611, FCGR2A rs1801274, and S100-Z rs7712957 in the allelic model. Associations between SNPs and the proportion of IBD-associated CRC in IBD patients were examined, and further investigation of additional SNPs and their association with the risk of morbidity is needed.

Abstract IA06: Colorectal cancer in inflammatory bowel disease

Abstract IA06: Colorectal cancer in inflammatory bowel disease

KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis.

Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; P<0.001) in patients with IBD-CRC compared to S-CRC. Both KRAS (RR=3.09, 95%CI 1.47-6.51; P=0.003) and TP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC.