Clonal Evolution in Breast Cancer Revealed by Single Nucleus Genome Sequencing

By Y. Wang, Jill Waters, Marco L. Leung, A. Unruh, Whijae Roh, Xiuqing Shi, Ken Chen, Paul Scheet, S. Vattathil, Han Liang and 6 more. Nature, 2014

1,019 citations recorded by the source corpus.

Sequencing studies of breast tumour cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumours. Here we developed a whole-genome and exome single cell sequencing approach called nuc-seq that uses G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumour nuclei from an oestrogen-receptor-positive (ER+) breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumour evolution and remained highly stable as the tumour masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Using targeted single-molecule sequencing, many of the diverse mutations were shown to occur at low frequencies (<10%) in the tumour mass. Using mathematical modelling we found that the triple-negative tumour cells had an increased mutation rate (13.3×), whereas the ER+ tumour cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.

Subfields: Cancer Research, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/02413d4d79fc4093ea1408556d60abc1a99a82c1

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Citations in the corpus

Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer (2017, neutral): “Genetic heterogeneity in breast cancer has been demonstrated at a single-cell resolution with high levels of genome coverage 5 .”
Subclonal diversification of primary breast cancer revealed by multiregion sequencing (2015, positive): “Genome sequencing has enabled analysis of clonal evolution in breast cancer through sequencing of primary tumor and metastasis pairs in a few cases 4,5 , sequencing of single cells 2,6 and xenograft models 7 as well as deep sequencing for subclonal mutations 1,3 .”
Design and Analysis of Single-Cell Sequencing Experiments. (2015, background): “Limiting the analysis to G2/M phase comes with the additional advantage of having duplicated material after replication of the entire genome (Wang et al., 2014).”
stLearn: integrating spatial location, tissue morphology and gene expression to find cell types, cell-cell interactions and spatial trajectories within undissociated tissues (2020, background): “Efforts to spatially characterise the heterogeneity of subclonal cancers by multi-region sequencing exploited spatial patterns 57 from a single time point within a tumour tissue 58,59 .”
Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “A number of studies have revealed extensive genomic heterogeneity within primary breast tumors and changes in subclonal structure during systemic therapy (Balko et al., 2014; Gellert et al., 2016; Miller et al., 2016; Ng et al., 2015; Shah et al., 2012; Wang et al., 2014; Yates et al., 2015).”