Clonal evolution in breast cancer revealed by single nucleus genome sequencing

Yong Wang, Jill Waters, Marco L. Leung, Anna Unruh, Whijae Roh, Xiuqing Shi, Ken Chen, Paul Scheet, Selina Vattathil, Han Liang, Asha Multani, Hong Zhang, Rui Zhao, Franziska Michor, Funda Meric-Bernstam and Nicholas E. Navin ()
Additional contact information
Yong Wang: The University of Texas MD Anderson Cancer Center
Jill Waters: The University of Texas MD Anderson Cancer Center
Marco L. Leung: The University of Texas MD Anderson Cancer Center
Anna Unruh: The University of Texas MD Anderson Cancer Center
Whijae Roh: The University of Texas MD Anderson Cancer Center
Xiuqing Shi: The University of Texas MD Anderson Cancer Center
Ken Chen: The University of Texas MD Anderson Cancer Center
Paul Scheet: The University of Texas Graduate School of Biomedical Sciences
Selina Vattathil: The University of Texas Graduate School of Biomedical Sciences
Han Liang: The University of Texas MD Anderson Cancer Center
Asha Multani: The University of Texas MD Anderson Cancer Center
Hong Zhang: The University of Texas MD Anderson Cancer Center
Rui Zhao: Dana-Farber Cancer Institute, Harvard School of Public Health
Franziska Michor: Dana-Farber Cancer Institute, Harvard School of Public Health
Funda Meric-Bernstam: The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics
Nicholas E. Navin: The University of Texas MD Anderson Cancer Center

Nature, 2014, vol. 512, issue 7513, 155-160

Abstract: Abstract 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 (

Date: 2014
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DOI: 10.1038/nature13600

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