Has the risk of colorectal cancer in inflammatory bowel disease decreased?
ABSTRACT 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.
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ABSTRACT: Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.PLoS Genetics 02/2015; 11(2):e1004901. DOI:10.1371/journal.pgen.1004901 · 8.17 Impact Factor
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ABSTRACT: Colorectal carcinoma is an important cause of death in inflammatory bowel diseases, thus requiring surveillance for dysplasia in long-standing ulcerative colitis (UC). Females show a lower incidence probably related to hormonal factors; therefore, a role of estrogen receptors (ERs) has been supposed in carcinoma-associated colitis (CAC) development. Our aim was to identify ER beta/alpha expression in long-lasting pancolitis through each grade of dysplasia to carcinoma and, furthermore, to investigate the simultaneous epithelial apoptosis/proliferation. MATERIALS AND METHODS: Forty-eight patients affected by long-lasting pancolitis were retrospectively investigated. Samples were divided into four groups: UC, low-grade dysplasia/high-grade dysplasia (UC-HGD), and CAC. Normal colon samples were used as controls. ER-beta, ER-alpha, Ki-67, and TUNEL expression (labeling/H index) were evaluated by immunohistochemistry. RESULTS: ER-beta expression revealed an impressive reduction in CAC (10.4 ± 5.1; p < 0.001) compared to controls and UC (34.3 ± 3.1 and 26.8 ± 7.8, respectively), meanwhile ER-beta level in LGD (29.4 ± 3.7) was comparable to UC. As far ER-beta/ER-alpha mean value ratio revealed a progressive reduction. Ki67 demonstrated a progressive significant increase from UC until CAC (37.9 ± 6.4 < 45.7 ± 6.2 < 60.6 ± 5.2 < 71.1 ± 5.1; p < 0.001). Apoptotic index (TUNEL) revealed a strong fall in UC-HGD and CAC. CONCLUSIONS: ER-beta fall could be considered as a biomarker of UC-dysplasia progression. It occurs in HGD and overt neoplasia, while in LGD shows a normal expression. At the moment, we are unable to use this tool in the clinical practice to predict tumor progression, but it would be appropriate to encourage ER expression investigations in large samples for the interesting perspectives of application. KEYWORDS: colorectal carcinoma; dysplasia; estrogen receptors; pancolitis; ulcerative colitisScandinavian Journal of Gastroenterology 08/2015; 50(8):1002-10. · 2.33 Impact Factor
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ABSTRACT: Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). The association between IBD and CRC is well supported, but reported risk estimates vary widely. Although recent evidence from population-based studies reports a decline in risk, CRC accounts for 10-15% of all deaths in IBD. The potential causes of recent epidemiological trends and the real magnitude of risk of CRC in IBD are subjects of debate. The molecular pathway leading to CRC differs from the classic adenoma-to-CRC sequence. Chronic inflammation contributes to the development of low- and high-grade dysplasia which may further convert into CRC. Patients with a young age at onset, long-standing and extensive colitis with severe inflammatory burden, a family history of sporadic CRC, and concomitant primary sclerosing cholangitis are at greatest risk. The CRC risk in patients with colonic Crohn's disease is similar to that of ulcerative colitis. IBD-associated CRC can frequently be detected at late stages and at a younger age. The long-term prognosis of CRC may be poorer in patients with IBD than in those with sporadic CRC. Regular surveillance colonoscopies may permit earlier detection of CRC, with a corresponding improved prognosis. The interval between surveillance colonoscopies is dependent on each patient's personal risk profile. © 2014 S. Karger AG, Basel.Digestive Diseases 01/2015; 33(1):52-7. DOI:10.1159/000368447 · 1.83 Impact Factor