This study introduces wellDR-seq, a novel, high-throughput method for simultaneously co-profiling single-cell whole genomes and transcriptomes, which offers superior performance compared to previous methods. This technique was applied to analyze Estrogen-Receptor-positive (ER+) breast cancer tumors, enabling the identification of potential luminal hormone-responsive cells as the cell of origin and tracing clonal lineages. The research further examines genotype-phenotype relationships, finding that while large copy-number alteration (CNA) segments show near-linear correlations with gene expression, there is significant variation at the individual gene level, leading to the identification of both dosage-sensitive and dosage-insensitive genes. Moreover, the study reveals that many differentially expressed genes between subclones are regulated independently of the subclonal CNAs, revealing a complex genetic landscape in breast cancer progression.

References:

• Wang, Kaile, et al. "Coalescing single-cell genomes and transcriptomes to decode breast cancer progression." Cell (2025).