Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that increases the lifetime risk of developing colorectal cancer (CRC) by almost two-fold. Our previous work has shown that aneuploidy in IBD surveillance biopsies is predictive of progression to CRC, however the extent of this aneuploidy, when it arises, and whether immune surveillance restricts progression remain incompletely determined.

We performed a spatially-resolved multi-omic analysis of the entire colon of two patients with ulcerative colitis (UC), and surveillance biopsies taken up to 5 years prior. In patient PX1 the colon was removed due to CRC in the ascending segment, whereas patient PX2 was cancer-free (although they had multiple pre-cancerous lesions previously removed during surveillance). For the colectomy specimens we performed low-pass whole genome sequencing (lpWGS) of 95 (PX1) and 44 (PX2) biopsies, and T-cell receptor sequencing (TCRseq) of 22 (PX1) and 41 (PX2) biopsies. An additional 25 (PX1) and 21 (PX2) formalin-fixed paraffin-embedded biopsies were profiled using both lpWGS and TCRseq.

We found extensive spread of highly aneuploid clones in both colons. In PX1, the clone containing the cancer-associated TP53 mutation was detected in almost every bowel segment. Analysis of archival colonic biopsies revealed that certain aneuploid clones were present for many years before removal of the colon. TCRseq revealed a median of 525 (PX1) and 455 (PX2) unique clonotypes per biopsy. PX2 showed incremental increase in TCR diversity along the bowel, consistent with higher inflammation in the left colon that is typical of UC. After excluding putative tissue-resident T-cell clonotypes that were found in >50% of biopsies, we found that PX1 had a greater degree of TCR overlap between biopsies than PX2 (median pairwise Morisita of 0.037 vs 0.014), consistent with more widespread field cancerisation in the PX2 bowel. Akin to the “patchwork” of epithelial clones around the bowels, we found that many T-cell clonotypes were discontiguous in nature, often with no clear co-localisation with genomic alterations. However, in PX1 there was strong concordance between the TCR repertoire and the presence of the TP53 mutant clone, suggestive of a T-cell response to a neo-antigen within this clone. We found that the PX1 tumour had distinct TCR clonotypes to the rest of the bowel (including pre-cancerous dysplastic lesions), suggesting immune escape, leading to a differential immune response, was associated with progression to cancer.

We reveal pan-colon field cancerisation in IBD, suggesting that there is a large “window of opportunity” in time and space for early detection and management of CRC risk. The T-cell repertoire evolves with the cancerised field, suggesting immune modulation could be a route to intercept cancer development.