Novel insights into breast cancer copy number genetic heterogeneity revealed by single-cell genome sequencing

Abstract

Copy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse.

MYCcontrols metastatic heterogeneity in pancreatic cancer

“…In this respect, it is noteworthy that MYC amplifications in human PDAC were far more common in metastases than primary tumors, including one case in which we were able to trace a metastatic lesion directly to a MYC-amplified subclone in the primary tumor. Collectively, these results suggest that subclonal MYC amplifications, which have been observed in human primary tumors, provide a selective advantage during metastatic progression (70,71). As one of the best-studied oncogenes, MYC has been associated with multiple tumorpromoting activities (67).…”

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer

“…Beyond assessing the transcriptome, single-cell DNA sequencing approaches have been developed and used to identify subpopulations of cells that express unique mutational and CNA patterns in therapeutically actionable genes in a given breast tumor [ 224 ]. These findings have clear clinical implications as different subpopulations will be likely be uniquely sensitive or resistant to specific therapeutic regimens and contribute to the evolution of the tumor and therapeutic sensitivity.…”

Breast Cancer Heterogeneity and Response to Novel Therapeutics

“…Moreover, sequencing studies highlighted the genetic differences between primary tumors and metastases [21]. Genomic studies at single cell level showed profound genetic heterogeneity and extensive clonal diversity in breast cancer [22,23], as well as heterogeneity in copy number alterations of genes and regions with known biological relevance in breast cancer, such as genes associated with metastasis and therapeutic response [24].…”