Polyclonal origins of human premalignant colorectal lesions

Cancer is generally thought to be caused by expansion of a single mutant cell. However, some analyses of early colorectal cancer lesions suggest that these tumors start not from a monoclonal expansion of a single cell, but rather from expansion of multiple, genetically distinct cell populations. Polyclonal tumor initiation is difficult to observe in patient samples because it requires profiling early-stage lesions that have not yet undergone clonal selective sweeps. Therefore, to study the clonality of early colorectal cancer initiation, we collected normal colorectal mucosa, benign and dysplastic premalignant polyps, and malignant adenocarcinomas (127 samples) from six individuals with familial adenomatous polyposis (FAP). Individuals with FAP have a germline heterozygous APC mutation, increasing their risk of colorectal cancer and leading to large numbers of premalignant polyps by early adulthood. Through analysis of whole-genome and/or whole-exome sequencing data of colectomy samples, we found that many premalignant polyps (40% with benign histology, 26% with dysplasia) were composed of multiple genetic lineages that diverged early and therefore were likely polyclonal. Our results have important implications for early neoplastic events and tumor heterogeneity; they further suggest that cell-intrinsic growth advantages may not be the only cause of tumor initiation.