The Evolution Of Sporadic Colorectal Adenomas: Copy Number Alterations (Cna) In Polyp Progressors Vs Non-Progressors

Introduction 1 in 10 people in the UK have a detectable adenoma in the bowel wall. Most adenomas are asymptomatic and detected incidentally during national screening and surveillance programmes. People who have adenomas detected and removed are considered at an increased risk of colorectal cancer (CRC), with risk calculations based on adenoma size and multiplicity. Our current risk stratification model is unspecific and results in many patients having unnecessary surveillance procedures. We hypothesise that prognostic biomarkers can be found through molecular analysis of adenomas removed at index colonoscopy, and there is a key role for copy number alteration accrual in adenoma progression. A cost-effective test to more accurately define the cohort of patients that will never progress to CRC would reduce the burden of procedures on both the patient and NHS. Methods FFPE adenoma tissue resected from patients who subsequently developed CRC (progressors) and matched adenomas from patients who remained cancer-free for 5+ years from the date of polypectomy (non-progressors) from a single-centre hospital archive (2008–2014) were analysed using low pass whole genome sequencing (LP-WGS). All adenomas were sequenced to a depth of >0.1x on an Illumina platform and CNA burden was investigated. Results In this case-control study, progressors n=12 have a greater CNA burden than non-progressors n=37, with >0.05% of the genome altered in progressors and <0.01% in non-progressors, p=0.292. The number of distinct copy-number segments were analysed to compare the presence of candidate CNAs. Gains were seen in chromosomes 7, 9 and 12 (>25%) and losses in 18 (>10%) in the progressor cohort. In comparison, minimal chromosomal changes were seen in non-progressors. Conclusions Adenomas from people who subsequent progressor to cancer may have a greater percentage of the genome altered when compared to non-progressors, with the majority of non-progressor adenomas having little or no genomic alterations. Larger sample sizes are required to confirm this. In the future, it is conceivable that patients with high burden of genomic alterations in their adenomas would be offered more intensive follow-up surveillance that low-burden adenoma patients.