A Pan-Cancer Single-Cell Analysis of Intratumoral Copy-Number Diversity and Evolution

Vollständiger Abstract

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Abstract Aneuploidy is a hallmark of human tumors. Although patient-level copy-number alteration (CNA) differences have been investigated extensively in large cohorts, their intratumoral heterogeneity remains understudied. In this study, 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 sequencing of six samples. In many cancer types, increased subclonal diversity was associated with higher CNA burden, whole-genome doubling (WGD), 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. Significance: This study presents one of the largest pan-cancer single-cell DNA sequencing analyses, profiling intratumoral copy-number heterogeneity across seven major cancer types. The data identified punctuated evolution, clonal origins, subclonal WGD, spatial heterogeneity, and associations between copy-number and transcriptional diversity, with implications for both cancer diagnosis and treatment.