Coalescing single cell aneuploidy and transcriptomes at scale 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, the first 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 larger chromosomal segments and extensive variation at the single gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes. We also identified 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.