OP38 Developing a Cost-Effective Genomic Biomarker of Cancer Risk in Patients with Ulcerative Colitis using Low-Pass Whole Genome Sequencing of Unselected Endoscopic Biopsies: A Case-Control Study

Al Bakir, I.(1);Curtius, K.(1);Smith, K.(1);Kopczynska, M.(1);Moorghen, M.(2);Hart, A.(3);Graham, T.(1)

(1)Queen Mary University of London, Barts Cancer Institute, London, United Kingdom;(2)St. Mark's Hospital, Pathology Department, Harrow, United Kingdom;(3)St. Mark's Hospital, Gastroenterology Department, Harrow, United Kingdom


Patients with ulcerative colitis (UC) are enrolled into surveillance programs for the early detection of colorectal cancer (CRC). However, most patients under surveillance are low-risk and never progress to CRC, while a significant proportion of CRCs in UC form without a preceding confirmed diagnosis of dysplasia. High resolution chromosomal copy-number alteration (CNA) analysis of unselected formalin-fixed paraffin embedded biopsies taken at surveillance colonoscopies using low pass whole genome sequencing (lpWGS) offers an appealing approach to CRC stratification.


We conducted a retrospective case-control study to compare the CNA burden in four unselected non-neoplastic left-sided colorectal biopsies from patients with E2/E3 UC derived 1-5 years prior to HGD/CRC detection (cases), with that of biopsies from patients who subsequently remained HGD/CRC-free for at least 5 years (controls). The two patient groups were matched by age, gender, duration of IBD and PSC status. lpWGS was performed using a standardised pipeline for epithelial enrichment, DNA extraction, library preparation, next generation sequencing and bioinformatic analysis.


476 biopsies, derived from 42 cases and 77 controls, were analysed. Nearly 80% of patients had a detectable CNA in at least one of their biopsies, with the maximal CNA burden in a typical biopsy involving a median 1.1% of that biopsy’s genome. The CNA burden was significantly greater in the rectum compared to the sigmoid colon and descending colon. The most common CNA events were losses of between 1-30 megabases involving the sub-telomeric regions of chromosomes 5-9 and 22, which were found in similar proportion in both case and control biopsies. However, losses extending beyond sub-telomeric regions, as well as copy number gains, were found more frequently in cases biopsies (p<0.0001). The most discriminating CNA event was the presence of such a loss extending beyond subtelomeric regions in any of the patient’s four biopsies, with a high specificity exceeding 0.95 (see Kaplan-Meier plot). ROC analysis demonstrates that lpWGS output has a fair level of accuracy at predicting future HGD/CRC risk (AUC 0.73).


We identified multiple biopsies, predominantly in cases, with a surprisingly marked CNA burden involving over 10% of the genome, highlighting the fluid phenotype-genotype relationship. Non-dysplastic colitic epithelium can bear a significant burden of CNAs and maintain phenotypic stability for years without neoplastic transformation. Remarkably, by analysing the CNA burden of only four random biopsies, derived from less than 0.05% of the colonic surface area, we can significantly discriminate between case and control cohorts.