Polyclonal origins of human premalignant colorectal lesions

Cancer is generally thought to be caused by expansion of a single mutant cell¹. However, analyses of early colorectal cancer lesions indicate that tumours may instead originate from several genetically distinct cell populations^2,3. Detecting polyclonal tumour initiation is challenging in patients, as it requires profiling early-stage lesions before clonal sweeps obscure diversity. To investigate this, we analysed normal colorectal mucosa, benign and dysplastic premalignant polyps and malignant adenocarcinomas (123 samples) from six individuals with familial adenomatous polyposis. Individuals with familial adenomatous polyposis have a germline heterozygous APC mutation, predisposing them to colorectal cancer and numerous premalignant polyps by early adulthood⁴. Whole-genome and/or whole-exome sequencing showed that many premalignant polyps-40% with benign histology and 28% with dysplasia-were composed of several genetic lineages that diverged early, consistent with polyclonal origins. This conclusion was reinforced by whole-genome sequencing of single crypts from polyps in further patients that showed limited sharing of mutations among crypts within the same lesion. In one case, several distinct APC mutations co-existed in different lineages of a single polyp, consistent with polyclonality. These findings reshape our understanding of early neoplastic events, demonstrating that tumour initiation can arise from the convergence of diverse mutant clones. They also indicate that cell-intrinsic growth advantages alone may not fully explain tumour initiation, highlighting the importance of microenvironmental and tissue-level factors in early cancer evolution.