Clonal evolution of colorectal cancer in IBD

Abstract

Optimizing the management of colorectal cancer (CRC) risk in IBD requires a fundamental understanding of the evolutionary process underpinning tumorigenesis. In IBD, clonal evolution begins long before the development of overt neoplasia, and is probably accelerated by the repeated cycles of epithelial wounding and repair that are characteristic of the condition. Here, we review the biological drivers of mutant clone selection in IBD with particular reference to the unique histological architecture of the intestinal epithelium coupled with the inflammatory microenvironment in IBD, and the unique mutation patterns seen in IBD-driven neoplasia when compared with sporadic adenomas and CRC. How these data can be leveraged as evolutionary-based biomarkers to predict cancer risk is discussed, as well as how the efficacy of CRC surveillance programmes and the management of dysplasia can be improved. From a research perspective, the longitudinal surveillance of patients with IBD provides an under-exploited opportunity to investigate the biology of the human gastrointestinal tract over space and time.

Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis

“…Patients with IBD have an increased risk of colorectal synchronous/metachronous malignancies arising from a field of marked chronic inflammation and closely linked to the extent, duration, and severity of inflammation. (24) In keeping with this, the present study demonstrated that biliary malignancies in patients with PSC were associated with the severity of bile duct inflammation, PBG hyperplasia, and duct wall thickening in the same duct. In PSC-affected ducts, chronic inflammation induces BTSC proliferation and subsequent mucinous metaplasia in PBGs (9) ; moreover, inflammation determines the emergence of SOX9 + /CFTR -(cystic fibrosis transmembrane conductance regulator) immature cells instead of normal mature cholangiocytes (CFTR + /secretin receptor + ) in surface biliary epithelium.…”

“…IBD is clinically and pathogenetically associated with PSC. Patients with IBD have an increased risk of colorectal synchronous/metachronous malignancies arising from a field of marked chronic inflammation and closely linked to the extent, duration, and severity of inflammation . In keeping with this, the present study demonstrated that biliary malignancies in patients with PSC were associated with the severity of bile duct inflammation, PBG hyperplasia, and duct wall thickening in the same duct.…”

“…Translating the IBD tumorigenic model in PSC, these observations indicate that the biliary epithelium in PSC may show aspects of “field cancerization”. The phenomenon of field cancerization represents the preconditioning of a large area of epithelium to the future development of neoplastic lesions and has been associated with synchronous carcinogenesis in IBD . Chronic inflammation is critical for field cancerization because it induces somatic mutations or epigenomic alterations and favors those cells (clones) best adapted to the inflamed microenvironment based on apoptosis resistance and replicative capability …”

“…In IBD‐related colorectal cancer, field cancerization derives from intestinal stem cells within crypts, given their role in epithelial regeneration and their long life span . A putative origin of field cancerization in PSC could be the Sox9 + cell niche within PBGs.…”

“…The phenomenon of field cancerization represents the preconditioning of a large area of epithelium to the future development of neoplastic lesions and has been associated with synchronous carcinogenesis in IBD. (24) Chronic inflammation is critical for field cancerization because it induces somatic mutations or epigenomic alterations and favors those cells (clones) best adapted to the inflamed microenvironment based on apoptosis resistance and replicative capability. (24) In IBD-related colorectal cancer, field cancerization derives from intestinal stem cells within crypts, given their role in epithelial regeneration and their long life span.…”