Colorectal Lesions Arise from Convergence of Distinct Mutant Clones

Technical barriers to studying the earliest steps of human tumor evolution have limited the understanding of how neoplasms arise, reinforcing the view that tumor initiation typically begins from a single, transformed cell. Isolated reports in colorectal cancer (CRC) have suggested an alternative, polyclonal origin, but a systematic assessment is lacking. Familial adenomatous polyposis (FAP), a hereditary CRC predisposition syndrome marked by the formation of numerous adenomas, represents an ideal setting to dissect the question of whether tumor initiation is mono- or polyclonal. To do this, Van Egeren, Schenck, Khan, Horning, Mo, Weiß and colleagues profiled 123 samples encompassing normal mucosal tissue and benign and dysplastic polyps from 6 patients with FAP using bulk whole-genome and whole-exome sequencing. As expected, polyps carried oncogenic alterations in known CRC drivers, most prevalent in APC and KRAS, confirming the genetic association with polyp initiation in FAP patients. Notably, several lesions included more than one independent APC mutation, suggesting multiple lineages expanded concurrently within one polyp. In fact, 40% of benign and 28% of dysplastic polyps showed signs of polyclonal initiation, suggesting they are not the results of expansion of a single epithelial cell. However, selective sweeps may eventually result in the monoclonal conversion of such a previously polyclonal lesion. These findings revise prevailing models of how colorectal tumors begin and could have important implications for early detection strategies and therapeutic interventions. Extending this work to sporadic CRC and resolving how microenvironmental factors shape coexistence, competition or cooperation of early clones will be essential. The study sets the stage for a deeper examination of tumor initiation as a multicellular process and opens a new line of inquiry into the very beginning of cancer development.Van Egeren D, Schenck RO, Khan A, Horning AM, Mo S, Weiß CL, et al. Polyclonal origins of human premalignant colorectal lesions. Nature 2025 Nov 25 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.