Quantifying cell divisions along evolutionary lineages in cancer

Cell division drives somatic evolution but is challenging to quantify in human tissues. Here, we develop a framework to count cell divisions with DNA replication-related mutations in polyguanine homopolymers. We apply the method in two different scenarios. First, analyzing 505 samples from 37 patients, we study the milestones of colorectal cancer evolution. We find that tumor founder cells divide at similar rates as normal intestinal stem cells over a patient’s lifetime. Primary tumors diversify at ~250 divisions from the founder cell, while distant metastasis divergence occurs significantly later, at ~500 divisions. Notably, distant but not lymph node metastases share a common origin with primary tumor regions that have undergone surplus divisions, tying subclonal expansion to metastatic capacity. Second, we analyze a cohort of 73 multifocal lung cancers with ambiguous origins. We show that the cell division burden of the tumors’ common ancestor distinguishes independent primary tumors from intrapulmonary metastases and correlates with patient survival. Metastatic capacity is tied to more extensive proliferation, mirroring our results in colorectal cancer. The cell division history of human cancers contains valuable biological and clinical information and can be effectively interrogated with our simple framework.