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

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Understanding breast cancer progression requires simultaneous analysis of single-cell genomes and transcriptomes.
• Current methods lack the resolution to link genotype and phenotype at the single-cell level for complex diseases like breast cancer.

Purpose of the Study:

• To develop and validate a high-throughput, high-resolution method for simultaneous single-cell genome and transcriptome profiling.
• To investigate the cell of origin and genotype-phenotype relationships in estrogen-receptor-positive breast cancer.

Main Methods:

• Development of wellDR-seq, a novel method for simultaneous genome and transcriptome profiling of thousands of single cells.
• Application of wellDR-seq to 33,646 single cells from 12 estrogen-receptor-positive breast cancer patients.

Main Results:

• Identification of ancestral subclones with a luminal hormone-responsive lineage, suggesting a potential cell of origin in multiple patients.
• Characterization of subclone-level gene-dosage relationships, revealing near-linear correlations in large chromosomal segments and single-gene variations.
• Discovery of dosage-sensitive and dosage-insensitive genes, including known breast cancer genes and sporadic copy-number aberrations in non-cancer cells.

Conclusions:

• wellDR-seq provides unprecedented insight into single-cell genomics and transcriptomics in breast cancer.
• The findings elucidate complex copy number-gene expression relationships, advancing the understanding of breast cancer progression and potential origins.