Single-Cell Sequencing Analysis Characterizes Common and Cell-Lineage-Specific Mutations in a Muscle-Invasive Bladder Tumor

Cancers arise through an evolutionary process, in which cell populations are subjected to selection; however, to date, the process at a single-cell level remains unknown. Here we carried out single-cell exome sequencing of 66 individual tumor cells from a muscle-invasive bladder transitional cell carcinoma (TCC). Analyses of the somatic mutant allele frequency spectrum and clonal structure revealed that the tumor cells were derived from a single ancestral cell, but that subsequent evolution occurred, leading to two distinct tumor cell subpopulations. By analyzing recurrently mutant genes in an additional 99 TCC tumors, we identified genes that might play roles in both the maintenance of the ancestral clone and in the muscle-invasive capability of subclones of this bladder cancer. This work provides a new way of investigating the genetic details of tumoral changes at the single-cell level and a new way for assessing cancer evolution at a cell-population level.