Segregating DNA lesions point to high selective advantage of tumor initiating cells.

The complications with identifying cells at the origin of cancer and tracking their early divisions impede studies of cancer initiation. Recently, it was shown that some DNA lesions generated by a pulse of damage-inducing mutagen persist over multiple rounds of replication. Segregation of DNA lesions in the early genealogy of an expanding clone leaves a statistically interpretable footprint of cancer initiating events. Specifically, it allows for estimating the number of cell divisions between the initiating DNA lesion and the most recent common ancestor of the tumor. Here, we analyze footprints of segregating lesions from a previously published experimental mouse system, as well as post-chemotherapy human metastatic tumors and the blood of chemotherapy treated patients. In all contexts, clones tend to start early, usually within the span of 4 cell generations from mutagen exposure. Using a branching process model, we show that fitness advantage of early cancer drivers exceeds 30%, with each early division leading to at least 1.3 self-renewing cells. We highlight an example of a blood-derived single cell phylogeny with major subclones separated by just two cell divisions. Broadly, our approach allows inference of tumor initiation and growth parameters based on events preceding the most recent common ancestor of the initiating clone as opposed to characteristics of fully grown tumors.