About 5% of colorectal adenomas are estimated to progress to colorectal cancer (CRC). However, it is important to identify which adenomas actually carry a high-risk of progression, because these serve as intermediate endpoints for e.g. screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high-risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of CAE's in advanced and non-advanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 non-advanced and 177 advanced) using Multiplex Ligation-dependent Probe Amplification or low-coverage whole genome DNA sequencing. Alterations in two or more CAE's were considered to mark adenomas as high-risk. Two or more CAE's were overall present in 25% (95%CI 19.0-31.8) of advanced adenomas; 23% (11/48), 36% (12/33) and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the non-advanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAE's, indicating that only a subset of these lesions is to be considered high-risk. Non-advanced adenomas have very low prevalence of CAE's, although those with CAE's should be considered high-risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype.
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