Measuring single cell divisions in human cancers from multi-region sequencing data

Abstract

Cancer is driven by complex evolutionary dynamics involving billions of cells. Increasing effort has been dedicated to sequence single tumour cells, but obtaining robust measurements remains challenging. Here we show that multi-region sequencing of bulk tumour samples contains quantitative information on single-cell divisions that is accessible if combined with evolutionary theory. Using high-throughput data from 16 human cancers, we measured the in vivo per-cell point mutation rate (mean: 1.69x10-8 bp per cell division) and per-cell survival rate (mean: 0.57) in individual patient tumours from colon, lung and renal cancers. Per-cell mutation rates varied 50-fold between individuals, and per-cell survival rates were between nearly-homeostatic and almost perfect cell doublings, equating to tumour ages between 1 and 19 years. Furthermore, reanalysing a recent dataset of 89 whole-genome sequenced healthy haematopoietic stem cells, we find 1.14 mutations per genome per cell division and near perfect cell doublings (per-cell survival rate: 0.96) during early haematopoietic development. Our analysis measures in vivo the most fundamental properties of human cancer and healthy somatic evolution at single-cell resolution within single individuals.