Risk prediction of metachronous colorectal cancer from molecular features of adenomas: a nested case-control study.

Current morphological features defining advanced adenomas (size ≥10 mm, high-grade dysplasia or ≥25% villous component) cannot optimally distinguish individuals at high-risk or low-risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy number alterations (CNAs) are associated with adenoma-to-carcinoma progression. We aimed to evaluate whether these molecular features can better predict an individual's risk of me-CRC than the morphological advanced adenoma features. In this nested case-control study, 529 individuals with a single adenoma at first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy number profiles were determined, by low-coverage whole genome sequencing. Prevalence of CNAs in advanced and non-advanced adenomas and its association (odds ratios; ORs) with me-CRC was assessed. For the latter, cases (with me-CRC) were matched to controls (without me-CRC) on follow-up, age and sex. CNAs associated with adenoma-to-carcinoma progression were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. Me-CRC was statistically significantly associated, also after adjustment for other variables, with age at baseline (OR 1.14; 95% CI 1.03-1.26; p=0.012), advanced adenomas (OR 2.46; 95% CI 1.50-4.01; p<0.001) and with the presence of ≥3 DNA copy number losses (OR 1.90; 95% CI 1.02-3.54; p=0.043). Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger.