Using a novel method for single-cell DNA sequencing, researchers have revealed for the first time that triple-negative breast cancers undergo continued genetic copy number changes during tumour growth.
Triple-negative breast cancers
Aneuploidy is a key feature of human breast cancers. It is particularly prevalent amongst patients with triple-negative breast cancer (TNBC) harbouring TP53 mutations. While researchers have well characterised the molecular mechanisms of aneuploidy, when and how chromosomal arrangements emerge and are maintained during tumour growth remains unclear.
A long-standing paradigm for tumour progression suggests that mutations and chromosomal aberrations accumulate gradually over time, leading to more malignant stages of cancer. An alternative model – punctuated copy number evolution (PCNE) – assumes that many chromosomal rearrangements arise together during early tumour evolution. Researchers have reported evidence for this model in breast tumours, colon cancer and prostate cancer. Previous work has also found that PCNE is common in patients with TNBC. However, researchers have yet been able to ascertain whether copy number profiles continue to evolve after the initial catastrophic event.
In this study, published in Nature, researchers developed a new single-cell, single-molecule DNA-sequencing method – acoustic cell tagmentation – to explore chromosome evolution in patients with TNBC. They performed copy number analysis of 16,178 single cells from 8 human TNBCs and 4 cell lines.
The results revealed that breast tumours and cell lines comprised a large number of subclones that could be organised into a few major subclones. Through evolutionary analysis, the team found that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability. This period was followed by ongoing copy number evolution during the primary tumour expansion. The team also confirmed that TNBC cell lines continued to accumulate changes when cultured in the laboratory, which has important implications for preclinical research.
Understanding how TNBCs evolve over time may provide insights into why treatments are not always effective. The team hope in the future to determine whether the number of genetic changes a tumour undergoes is predictive of clinical outcomes. They also aim to investigate additional cancer types to understand if this model of cancer evolution may be broadly applicable beyond TNBCs.
Image credit: By Science Photo Library – canva.com