A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution

Abstract Aneuploidy is a hallmark of human tumors. While patient-level copy number alteration (CNA) differences have been investigated extensively in large cohorts, their intratumoral heterogeneity remains understudied. Here, we conducted a pan-cancer analysis of 94 human tumors at single cell resolution, representing seven cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovarian. Single-cell copy number profiling was used to analyze 62,646 aneuploid cells, in addition to bulk exome sequencing of most patients and single-nucleus RNA-seq of 6 samples. In many cancer types, increased subclonal diversity was associated with higher CNA burden, whole genome doubling, TP53 mutations, and increased geographic diversity. Cancer cells from each patient shared a set of truncal CNAs, suggesting evolution from a single ancestral cell. Many tumors accumulated CNAs in bursts of evolution, suggesting that punctuated evolution is common in diverse cancer types. This study greatly improves our knowledge of intratumoral chromosome diversity across human cancers.