SAGES Magazine

THE SOUTH AFRICAN GASTROENTEROLOGY REVIEW 2023 | VOLUME 21 | ISSUE 1 | 5 Introduction Ulcerative colitis (UC) and Crohn’s disease (CD) represent the main phenotypes of inflammatory bowel disease (IBD), which are chronic relapsing and remitting inflammatory conditions of the gastrointestinal tract. The development of IBD is associated with westernization, with increasing incidence over recent decades being more pronounced in newly industrialized regions such as South America, North Africa, and Southeast Asia 1 . Although published data from sub-Saharan Africa (SSA) suggests that IBD is uncommon in the region 2, 3 , the most plausible explanation for these low rates is under-reporting of cases, with unpublished real-world data supporting an increase in the incidence. Furthermore, with an increasing population average lifespan, the prevalence of IBD globally is on the rise 4 , with the downstream effect of a parallel increase in the prevalence of colorectal cancer (CRC). It is well known that IBD affecting the colon is a major risk factor for CRC. Patients with UC have a 1.7 - 2.4 times increased risk of CRC compared to non-IBD controls 5, 6 . In CD the risk ranges from 1.4 - 4.5 times that in controls 6, 7 . However, recent data shows that there is steady decline in the prevalence of CRC in IBD patients. In UC the cumulative risk of CRC after 30 years was 18% in 2001 8 , compared to 7% in 2014 9 . This is attributed to improved screening and more effective immunosuppressive agents. Furthermore, compared to patients with sporadic CRC, patients with IBD- associated CRC are younger with a mean age of 66 years vs 72 years, have more right colonic CRC (37% vs 34%), and higher rates of synchronous and metachronous CRCs (3.2% vs 1.6%, and 1.7% vs 0.9%) respectively 10 . However, despite the declining rates of CRC in this group, these patients still have lower survivals rates, with poorer tumour differentiation, when compared with those with sporadic CRC, (HR 1.24 95% CI 1.19, 1.29) 11 . This imposes a significant burden in the management of IBD and is particularly important for SSA where an apparent increase in IBD is compounded by limited resources, and inadequate access to appropriate therapy. Pathogenesis of IBD-associated colon cancer Compared to sporadic CRC where the pathogenesis follows the well described adenoma-carcinoma sequence and is linked to a positive family history, as well as lifestyle factors, IBD-associated CRC develops through the inflammation-dysplasia-carcinoma sequence (Figure 1). Dysplasia occurs as a direct effect of chronic inflammation that can induce mutagenesis through the production of increased reactive oxygen species, reduced antioxidant capacity, and lipid peroxidation, ultimately resulting in oxidative DNA damage 12 . In terms of the dysplasia- carcinoma sequence the frequency and timing of these alterations differs in sporadic CRC compared to IBD- associated CRC 13 . While APC gene mutations or loss occur early and p53 mutations or loss occur late in sporadic CRC, the reverse is true in IBD-associated CRC 14 . Other contributory factors to the development of CRC include the gut microbiome 15, 16 and several epigenetic changes in the early phase of CRC 17 . Current perspectives on IBD-associated colorectal cancer IE Francis, G Watermeyer, M Setshedi Department of Medicine, Division of Gastroenterology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa Normal Early adenoma Intermediate adenoma Late adenoma Carcinoma Chronic inflammation Indefinite dysplasia Low-grade dysplasia High-grade dysplasia Carcinoma APC loss Aneuploidy, CpG island methylation, miRNA dysregulation Microsatellite instability, KRAS mutations, COX-2 activity SRC mutations DCC and DPC4 mutations p53 mutations Microbiome (biofilms, Fusobacterium nucleatum, pks+ E.coli, Bacteroides fragilis toxin) & environmental factors Aneuploidy, CpG island methylation, COX-2, microsatellite instability, miRNA dysregulation SRC mutations p53 mutations A. Sporadic colorectal cancer B. IBD-associated colorectal cancer p53 LOH, DCC mutations KRAS mutations APC loss Microbiome (biofilms, Fusobacterium nucleatum, pks+ E.coli, Bacteroides fragilis toxin) & environmental factors Figure 1: Molecular pathogenesis of IBD-associated colorectal cancer compared with sporadic CRC APC, adenomatous polyposis coli; COX-2, cyclooxygenase-2; DCC, deleted in colon cancer; DPC4, deleted in pancreatic cancer; KRAS, Kirsten rat sarcoma viral oncogene homolog; LOH, loss of heterozygosity; miRNA, microRNA; SRC, family of non-receptor tyrosine kinases. Adapted from Shah, S.C. and Itzkowitz S.H. 18 Correspondence Innocent Francis email: francisinno@gmail.com