Coalescing single-cell genomes and transcriptomes to decode breast cancer progression

Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.