Risk Of Colorectal Cancer In Inflammatory Bowel Disease Research Articles

Low coverage whole genome sequencing of low-grade dysplasia strongly predicts colorectal cancer risk in ulcerative colitis.

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.

Occurrence of Colorectal Cancer and the Influence of Medical Treatment in Patients With Inflammatory Bowel Disease: A Danish Nationwide Cohort Study, 1997 to 2015.

The risk of colorectal cancer (CRC) for patients with inflammatory bowel disease (IBD) has previously been investigated with conflicting results. We aimed to investigate the incidence and risk of CRC in IBD, focusing on its modification by treatment. All patients with incident IBD (n = 35,908) recorded in the Danish National Patient Register between 1997 and 2015 (ulcerative colitis: n = 24,102; Crohn's disease: n = 9739; IBD unclassified: n = 2067) were matched to approximately 50 reference individuals (n = 1,688,877). CRC occurring after the index date was captured from the Danish Cancer Registry. Exposure to medical treatment was divided into categories including none, systemic 5-aminosalicylates, immunomodulators, and biologic treatment. The association between IBD and subsequent CRC was investigated by Cox regression and Kaplan-Meier estimates. Of the IBD patients, 330 were diagnosed with CRC, resulting in a hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.03-1.28) as compared with the reference individuals. However, when excluding patients diagnosed with CRC within 6 months of their IBD diagnosis, the HR decreased to 0.80 (95% CI, 0.71-0.92). Patients with ulcerative colitis receiving any medical treatment were at significantly higher risk of developing CRC than patients with ulcerative colitis who were not given medical treatment (HR, 1.35; 95% CI, 1.01-1.81), whereas a similar effect of medical treatment was not observed in patients with Crohn's disease or IBD unclassified. Medical treatment does not appear to affect the risk of CRC in patients with IBD. The overall risk of developing CRC is significantly increased in patients with IBD as compared with the general population. However, when excluding patients diagnosed with CRC within 6 months of their IBD diagnosis, the elevated risk disappears.

Colorectal Cancer in Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously "invisible" flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time.

5-ASA and Chemoprevention in Inflammatory Bowel Disease: A Population-Based Analysis

Introduction: Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing and remitting inflammatory disease of the gastrointestinal tract. Colorectal cancer (CRC) is a well-documented complication of IBD and is associated with IBD severity, extent and duration. Treatment with 5-aminosalicylic acid (5-ASA) reduces the risk of CRC in IBD. Our objective was to test the association of cumulative exposure to 5-ASA on CRC risk. Methods: A retrospective cohort study was performed using a population-based IBD cohort derived from administrative health data in Saskatchewan, Canada. Data were from 1979 to 2011. Exposure to 5-ASA and CRC diagnosis during the study period were examined. CRC rates were compared between 5-ASA exposed and non-exposed groups using chi-square tests. Exposure to 5-ASA was evaluated using survival analysis. To account for differences in 5-ASA exposure, propensity scores (PS) based on IBD duration, immunomodulator (IM) and anti-TNF exposure, number of endoscopies, and decade of IBD diagnosis were used to match non-exposed to exposed patients. The Kaplan-Meier estimator was used to describe the time-to-event data and Cox proportional hazards regression models were used to test the association of exposure with CRC diagnosis. Analyses were stratified by type of IBD (UC, CD). Results: A total of 8821 IBD patients were included in the study, of which 289 (3.3%) developed CRC. In the CRC-free group, 73.9% (n = 6307) of patients had exposure to 5-ASA, whereas 61.9% (n = 179) had exposure in the CRC group. Figure 1 contains a Kaplan Meier curve for time-to-diagnosis of CRC for the exposure groups. In the PS-matched cohort, the hazard ratio (HR) was 2.56 (95% CI: [1.9, 3.5]) while controlling for gender, location (urban/sub-urban/rural), diagnosis and previous corticosteroid use. The risk of CRC diagnosis was higher in the UC sub-group (HR=3.54, 95% CI: [2.3, 5.5]) when compared to the CD sub-group (1.73, 95% CI: [1.1, 2.6]), controlling for gender, location and decade of diagnosis. A dose response survival model was developed to attempt to control for the duration of 5-ASA exposure on CRC rates, and the HRs were similar.Figure 1Conclusion: This population-based cohort study suggests a chemoprotective effect of 5-ASA exposure for CRC diagnosis amongst patients with IBD. A larger protective effect was observed amongst UC patients than CD patients.

Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal cancer (CRC), although the overall incidence of IBD-associated CRC has been diminishing in recent decades in western countries. As demonstrated in previous studies, the risk of CRC in IBD increases with longer duration, extent of colitis, a familial history of CRC, coexistent primary sclerosing cholangitis, and the degree of inflammation. The pathogenesis of CRC in IBD is poorly understood. Similar to sporadic CRC, IBD-associated CRC is a consequence of sequential episodes of genomic alteration. Multiple inter-related pathways, including immune response by mucosal inflammatory mediators, oxidative stress, and intestinal microbiota, are also involved the pathogenesis of IBD-associated CRC. Continuing colonic inflammation appears to be a factor in the development of CRC; therefore, anti-inflammatory agents such as 5-aminosalicylate compounds and immune modulators have been considered as potential chemopreventive agents. Colonoscopic surveillance is widely accepted as being effective in reducing the risk of IBD-associated CRC, although no clear evidence has confirmed that surveillance colonoscopy prolongs survival in patients with extensive colitis. The traditional recommendation has been quadrantic random biopsies throughout the entire colon; however, several guidelines now have endorsed chromoendoscopy with a target biopsy because of increasing diagnostic yields and reduced workloads for endoscopists and pathologists. New technologies such as narrow band imaging, confocal endomicroscopy, and autofluorescence imaging have not yet been confirmed as surveillance strategies in IBD.

Declining Risk of Colorectal Cancer in Inflammatory Bowel Disease

Recently reported risks of colorectal cancer (CRC) in inflammatory bowel disease (IBD) have been lower than those reported before 2000. The aim of this meta-analysis was to update the CRC risk of ulcerative and Crohn's colitis, investigate time trends, and identify high-risk modifiers. The MEDLINE search engine was used to identify all published cohort studies on CRC risk in IBD. Publications were critically appraised for study population, Crohn's disease localization, censoring for colectomy, and patient inclusion methods. The following data were extracted: total and stratified person-years at risk, number of observed CRC, number of expected CRC in background population, time period of inclusion, and geographical location. Pooled standardized incidence ratios and cumulative risks for 10-year disease intervals were calculated. Results were corrected for colectomy and isolated small bowel Crohn's disease. The pooled standardized incidence ratio of CRC in all patients with IBD in population-based studies was 1.7 (95% confidence interval [CI], 1.2-2.2 ). High-risk groups were patients with extensive colitis and an IBD diagnosis before age 30 with standardized incidence ratios of 6.4 (95% confidence interval, 2.4-17.5) and 7.2 (95% confidence interval, 2.9-17.8), respectively. Cumulative risks of CRC were 1%, 2%, and 5% after 10, 20, and >20 years of disease duration, respectively. The risk of CRC is increased in patients with IBD but not as high as previously reported and not in all patients. This decline could be the result of aged cohorts. The risk of CRC is significantly higher in patients with longer disease duration, extensive disease, and IBD diagnosis at young age.

Has the risk of colorectal cancer in inflammatory bowel disease decreased?

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) has been acknowledged for almost a century and is assumedly promoted by a chronic inflammation-driven carcinogenic process in the intestine in combination with a genetic predisposition. The magnitude of the risk of CRC in IBD remains a continuing subject of debate. The early, high risk estimates for CRC in IBD were most likely overestimated due to selected patient populations originating from tertiary referral centers with a disproportional high percentage of patients with severe disease. Later population-based studies calculating risk estimates from a broad spectrum of IBD patients have found the risk to be significantly lower. At present, there is evidence that IBD patients with longstanding and extensive disease with uncontrolled inflammation are those at increased risk. Additional, other recognized risk factors include early age at onset, family history of CRC, and concomitant primary sclerosing cholangitis. A significant amount of effort is put into identifying potential preventive factors of CRC in IBD, including surveillance programs and chemopreventive agents but the individual effect of these remains uncertain. Interestingly, recent studies have reported a decline in risk of CRC over time. Surveillance programs and the new treatment strategies, particular biological treatment might be part of the reason for the observed decline in risk of CRC in IBD over time but future studies will have investigate this assumption.

Inflammatory Bowel Disease-Associated With Colorectal Cancers in Korea: A Single-Center Experience

Although a colorectal cancer (CRC) is a well-known complication of inflammatory bowel disease (IBD), the epidemiology and characteristics of CRC associated with IBD in Asians are still unclear. We retrospectively reviewed the medical records of IBD patients who were registered at the Asan Medical Center from July 1989 to August 2012. Patients who were diagnosed with CRC at the time of or after diagnosis of IBD were identified. A total of 3575 patients with definite IBD (1877 with ulcerative colitis [UC] and 1698 with Crohn's disease [CD]), were enrolled and 25 patients diagnosed with IBD-associated colorectal adenocarcinoma (15 with UC and 10 with CD) were identified. There were 14 females (56%) and the median age at diagnosis of CRC was 43.1 years (interquartile range [IQR], 32.0-52.1 years). Two UC patients had combined primary sclerosing cholangitis. The median interval from IBD diagnosis to cancer diagnosis was 11 years (IQR, 5.1-16.8 years). Five patients (20%) were diagnosed with cancer at the time of IBD diagnosis. Three patients (12%) had synchronous lesions. The histologies of CRCs were as follows; moderately differentiated adenocarcinoma in 11 (44%), mucinous adenocarcinoma in 6 (24%), poorly differentiated adenocarcinoma in 4 (16%), well differentiated adenocarcinoma in 3 (12%), and signet ring cell carcinoma in 1 (4%). The stage distribution of cancer was as follows; I in 3 (12%), II in 8 (32%), III in 5 (20%) and IV in 9 (36%). The cumulative risk of CRC in IBD, UC and CD patients were 0.6%, 0.7% and 0.5%, respectively after 10 years and 5.8%, 5.1% and 7.2% respectively after 20 years. The IBD-associated CRC tends to show an advanced stage at diagnosis. The risk of CRC in Korean IBD patients appears to be comparable to that of Western IBD patients.

Colorectal cancer in inflammatory bowel disease: What is the real magnitude of the risk?

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) has been recognised since 1925 and still accounts for 10%-15% of deaths in IBD. IBD-associated CRC (IBD-CRC) affects patients at a younger age than sporadic CRC. The prognosis for sporadic CRC and IBD-CRC is similar, with a 5-year survival of approximately 50%. Identifying at risk patients and implementing appropriate surveillance for these patients is central to managing the CRC risk in IBD. The increased risk of colorectal cancer in association with IBD is thought to be due to genetic and acquired factors. The link between inflammation and cancer is well recognised but the molecular biology, immune pathobiology and genetics of IBD-CRC are areas of much ongoing research. This review examines the literature relating to IBD-CRC, focusing on the incidence of IBD-CRC and examining potential risk factors including age at diagnosis, gender, duration and extent of colitis, severity of inflammation, family history of sporadic CRC and co-existent primary sclerosing cholangitis (PSC). Confirmed risk factors for IBD-CRC are duration, severity and extent of colitis, the presence of co-existent PSC and a family history of CRC. There is insufficient evidence currently to support an increased frequency of surveillance for patients diagnosed with IBD at a younger age. Evidence-based guidelines advise surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis, with the interval for further surveillance guided by risk factors (extent of disease, family history of CRC, post-inflammatory polyps, concomitant PSC, personal history of colonic dysplasia, colonic strictures). There is a move away from using random colonic biopsies towards targeted biopsies aimed at abnormal areas identified by newer colonoscopic techniques (narrow band imaging, chromoendoscopy, confocal microendoscopy).

Dysplasia and cancer in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease associated with an increased risk of colorectal cancer (CRC). Although CRC occurs in a minority of IBD patients (1%), it carries a high mortality and accounts for 20% of IBD-related mortality. Established risk factors for the development of CRC in IBD include disease duration of 8 years or more, family history of CRC, extensive colitis and primary sclerosing cholangitis. Meticulous colonoscopy and anti-inflammatory medications can reduce the risk of developing CRC. The future of IBD surveillance involves the use of novel endoscopic techniques (chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy and autofluorescence) to enhance colonoscopic accuracy, in concert with chemopreventative medications to help reduce the risk of CRC in IBD.

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC) .

HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts

Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E(2) secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1alpha-induced cyclooxygenase-2 (COX-2) expression is the result of NF-kappaB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1alpha-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 +/- 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-beta-d-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1alpha to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.

Changes in Clinical Characteristics, Course, and Prognosis of Inflammatory Bowel Disease during the Last 5 Decades: A Population-Based Study from Copenhagen, Denmark

It remains uncertain whether the increasing incidence of inflammatory bowel disease (IBD) during the last decades has been accompanied by an alteration in the presentation, course, and prognosis of the disease. To answer this question, 3 consecutive population-based IBD cohorts from Copenhagen, Denmark (1962-2005), were assessed and evaluated. Phenotype, initial disease course, use of medications, cumulative surgery rate, standardized incidence ratio of colorectal cancer (CRC), and standardized mortality ratio (SMR) were compared in the 3 cohorts, which had a total of 641 patients with Crohn's disease (CD) and 1575 patients with ulcerative colitis (UC). From 1962 to 2005, the proportion of IBD patients suffering from CD increased (P < 0.001), time from onset of symptoms to diagnosis of CD decreased (P = 0.001), and median age at diagnosis of UC increased (P < 0.01). The prevalence of upper gastrointestinal involvement and pure colonic CD varied significantly between cohorts. UC patients diagnosed in the 1990s had a higher prevalence of proctitis, received more medications, and had a milder initial disease course than did previous patients. The surgery rate decreased significantly in CD but not in UC. The risk of CRC in IBD was close to expected over the entire period, whereas the mortality of patients with CD increased (overall SMR, 1.31; 95% CI, 1.07-1.60). Despite variations in the presentation and initial course of IBD during the last 5 decades, its long-term prognosis remained fairly stable. Treatment of IBD changed recently, and future studies should address the effect of these changes on long-term prognosis.

Inflammatory bowel disease in Ashkenazi Jews: implications for familial colorectal cancer

Inflammatory bowel disease (IBD) has a multifactorial etiology and includes ulcerative colitis (UC) and Crohn's disease (CD). Powerful epidemiologic and genetic studies have provided ample evidence that a subset of both CD and UC are attributable to a likely primary genetic etiology. This is evidenced by the recent identification of the IBD1 gene ( NOD2 ) mutations which show an association with susceptibility to CD. The IBD complex shows a significant increased frequency in Jews when compared to non-Jews. While there is an increased incidence of colorectal cancer (CRC) in patients with IBD, it nevertheless is important to realize that IBD likely accounts for no more than 1-3% of all cases of CRC in Ashkenazi Jews. Importantly, however, awareness of the increased CRC risk in IBD may aid immeasurably in preventive interventions. The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat, dysplastic tissue or dysplasia-associated lesions or masses (DALMs). An important model, but by no means an absolute one, for colon carcinogenesis in IBD follows progression from an absence of dysplasia, to indefinite dysplasia, to low-grade dysplasia, on to high-grade dysplasia, and ultimately to invasive CRC. This carcinogenic process relates to the disease duration with respect to the extent of colonic involvement and may also involve primary sclerosing cholangitis. Given this knowledge of an increased risk for CRC in UC and CD, surveillance colonoscopy should initially be performed 8-10 years after onset of symptoms as opposed to diagnosis, and it should be performed 1-2 years after 8 years of disease in patients with pancolitis or after 15 years in those with left-sided colitis. A search for dysplasia of colonic mucosa with biopsies performed in all four quadrants every 10 cm throughout the colon is exceedingly important. Additional biopsies should be taken of any flat lesions, masses, or strictures. Prophylactic colectomy may then be indicated when severe dysplasia is confirmed by knowledgeable pathologists.

Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice.

Although both sporadic colorectal cancer (CRC) and colitis-associated CRC arise from dysplastic precursor lesions and share several molecular alterations, the nature of the dysplasia and the frequency and timing of several of the key molecular changes differ enough to consider colitis-associated CRC a rather unique entity. To date, cancer surveillance in both ulcerative colitis and Crohn's colitis rests upon the detection of dysplasia. However, because there are considerable limitations to the detection and interpretation of dysplasia, there is a need for other molecular markers to complement the histologic analysis of dysplasia. Because patients with inflammatory bowel disease (IBD) undergo repeated, periodic surveillance colonoscopies, it affords an opportunity to study marker expression over time. Of the few markers that have been studied chronologically, aneuploidy, p53, and mucin-associated sialyl-Tn antigen expression each hold promise as markers of CRC risk in IBD. It will be important to study whether these markers, or other panels of gene or protein expression, can identify patients at highest risk for developing CRC in future clinical studies.