Abstract IA06: Colorectal cancer in inflammatory bowel disease

Inflammatory bowel disease (IBD), consisting mainly of ulcerative colitis and Crohn9s disease (CD), is characterized by chronic inflammation of the colon (and in the case of CD, other parts of the GI tract). As such, it is often considered the prototypical model of inflammation-associated carcinogenesis. After the well-known genetic syndromes that greatly predispose individuals to colorectal cancer (CRC), such as Lynch Syndrome and familial adenomatous polyposis (FAP), IBD is considered the third most common cause of high-risk CRC. Curiously, colitis-associated CRC (so-called CAC) shares several clinicopathological features with Lynch syndrome: CACs tend to affect young individuals, are often multifocal and/or affect the proximal colon, and frequently display mucinous and signet ring cell histology. Yet, to date, despite the identification of over 200 susceptibility genes for IBD itself, a germline genetic basis for human CAC has not been found. Recent studies suggest that the overall incidence of CAC is decreasing in recent years. Although the reasons are not known, this is likely due to a combination of better identification of dysplasia due to enhanced imaging technology, better removal of preneoplastic lesions, perhaps better control of inflammation with newer IBD medications, and possibly earlier surgery before CAC has a chance to develop. IBD itself is believed to occur in a genetically susceptible individual who gets exposed to certain environmental factors that trigger a chronic, often relentless, immune response. The paradigm for colorectal carcinogenesis in IBD holds that normal colorectal mucosa becomes exposed to an environmental insult (for example, following an intestinal infection, heavy use of NSAIDs, other unknown toxin), which, rather than resulting in restitution of normal colorectal health, develops into uncontrolled, chronic inflammation. After many years, and what is thought to be a recurring process of inflammation-induced cell proliferation and DNA damage, dysplasia and eventually cancer may arise. Several lines of clinical evidence support the role of chronic inflammation in CAC. Risk increases with greater severity of colonic inflammation (whether measured histologically or endoscopically), greater extent of colon involvement, and longer duration of disease. And for unclear reasons, the 7-8% of patients with IBD who have concomitant chronic inflammation of the intra- and extra-hepatic bile ducts (primary sclerosing cholangitis) are at the highest risk of CAC. However, there are several clinical observations that pose challenges to the simple dogma that inflammation begets CAC. For example, individuals with chronic proctitis, in whom only the rectum has been inflamed for many years, are at no greater risk of rectal cancer than the general population. Also, patients with IBD-PSC while being at the greatest risk of CAC, typically have very quiescent colitis with minimal inflammation. And, one would expect that suppressing inflammation with IBD medications over the years should lower the risk of CAC, yet this has not been easy to prove, and many patients who get CAC have been on longstanding anti-inflammatory and immune modulating medications. Like sporadic CRC, CAC arises from a dysplastic precursor lesion. The finding of a dysplastic lesion in a patient with IBD is perhaps the most important risk factor for future development of CAC. For the most part, the same genetic alterations that occur in the progression of sporadic adenomas to carcinoma also occur in CAC carcinogenesis. Some of the more important alterations occur with different frequency and different sequence between the two types of CRC. Most notably, APC mutations and LOH are early and very frequent in sporadic CRC but later and less frequent in CAC. Conversely, p53 alterations occur very early in CAC development, even in mucosa that is not frankly dysplastic, compared to sporadic carcinogenesis where it is often altered in later stage adenomas. Two recent studies conducted comprehensive analyses of genomic alterations in CAC compared to data from sporadic CRC reported by The Cancer Genome Atlas. Both studies confirmed the aforementioned observations of APC and p53. One of them also reported more frequent MYC expression in CAC, and rather unique expression of IDH1 in Crohn9s-associated CAC (Yaeger et al.), and the other, more frequent mutation of SOX9 and EP300 (WNT pathway), NRG1 (ERBB ligand) and IL16 (Robles et al.). In the latter study, approximately one third of CACs showed alterations that might be targeted by new therapeutic agents (IDH1 R132; amplification of FGFR1, FGFR2, ERBB2, mutations encoding BRAF V600E, and EML4-ALK mutation). Recent studies have demonstrated proof of concept that analysis of altered tumor-associated DNA in stool of patients with IBD may be a useful adjunct to the clinical management of neoplasia risk. To help sort out the role of various components of the immune system in CAC a large variety of animal models have been studied. For the most part, these models apply an inflammatory insult (DSS) with and without a carcinogen (AOM) in otherwise immune-intact mice, or in genetically modified mice with various cytokines or immune cell populations altered. These studies have elucidated many important mechanisms of inflammation-associated colon carcinogenesis, including the important observation that some animal models do not develop CAC in germ free environments but only do so in response to reintroducing commensal microbiota. It is hoped that by applying knowledge from animal models, cellular and organoid systems, cancer stem cell biology, and further human/translational investigations, a better understanding of CAC development and treatment will emerge. References Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med. 2015 Apr 9;372(15):1441-52 Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011 May;140(6):1807-16 Kisiel JB, Yab TC, Nazer Hussain FT, et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013 Mar;37(5):546-54 Robles AI, Traverso G, Zhang M, et al. Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology. 2016 Apr;150(4):931-43 Yaeger R, Shah MA, Miller VA, et al. Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease. Gastroenterology. 2016 Aug;151(2):278-287 Citation Format: Steven Itzkowitz. Colorectal cancer in inflammatory bowel disease. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA06.