Patients with inflammatory bowel disease have an increased risk of developing colorectal cancer, and this risk is related to disease duration, extent, and cumulative inflammation burden. Carcinogenesis follows the principles of Darwinian evolution, whereby somatic cells acquire genomic alterations that provide them with a survival and/or growth advantage. Colitis represents a unique situation whereby routine surveillance endoscopy provides a serendipitous opportunity to observe somatic evolution over space and time in vivo in a human organ. Moreover, somatic evolution in colitis is evolution in the ‘fast lane': the repeated rounds of inflammation and mucosal healing that are characteristic of the disease accelerate the evolutionary process and likely provide a strong selective pressure for inflammation-adapted phenotypic traits. In this review, we discuss the evolutionary dynamics of pre-neoplastic clones in colitis with a focus on how measuring their evolutionary trajectories could deliver a powerful way to predict future cancer occurrence. Measurements of somatic evolution require an interdisciplinary approach that combines quantitative measurement of the genotype, phenotype and the microenvironment of somatic cells–paying particular attention to spatial heterogeneity across the colon–together with mathematical modeling to interpret these data within an evolutionary framework. Here we take a practical approach in discussing how and why the different “evolutionary ingredients” can and should be measured, together with our viewpoint on subsequent translation into clinical practice. We highlight the open questions in the evolution of colitis-associated cancer as a stimulus for future work.

Background: Formalin fixation and paraffin embedding (FFPE) of patient material remains standard practice in clinical pathology labs around the world. Clinical archives of patient material near-exclusively consist of FFPE blocks. The ability to perform high quality genome sequencing on FFPE-derived DNA would accelerate a broad spectrum of medical research. However, formalin is a recognised mutagen and sequencing of DNA derived from FFPE material is known to be riddled with artefactual mutations. Results: Here we derive genome-wide mutational signatures caused by formalin fixation, and provide a computational method to correct mutational profiles for these formalin-induced artefacts. We show that the FFPE-signature is dominated by C>T transitions caused by cytosine deamination, and has very high similarity to COSMIC signature SBS30 (base excision repair deficiency due to inactivation mutations in NTHL1). Further, we demonstrate that chemical repair of formalin-induced DNA lesions, a process that is routinely performed as part of sequencing library preparation, leads to a signature highly similar to COSMIC signature SBS1 (spontaneous deamination of methylated cytosine). Next, we design FFPEsig, a computational method to remove the formalin-induced artefacts from mutational counts. We prove the efficacy of this method by generating synthetic FFPE samples using 2,780 cancer genomes from the Pan-Cancer Analysis of Whole Genome (PCAWG) project, and via analysis of FFPE-derived genome sequencing data from colorectal cancers. Conclusions: Formalin fixation leaves a predictable mutational footprint across the genome. The application of our FFPEsig software corrects the mutational profile for the influence of formalin, enabling robust mutational signature analysis in FFPE-derived patient material.