Clonal evolution in breast cancer revealed by single nucleus genome sequencing

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 br...

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Bibliographic Details
Published in:Nature (London) 2014-08, Vol.512 (7513), p.155-160
Main Authors: Wang, Yong, Waters, Jill, Leung, Marco L, Unruh, Anna, Roh, Whijae, Shi, Xiuqing, Chen, Ken, Scheet, Paul, Vattathil, Selina, Liang, Han, Multani, Asha, Zhang, Hong, Zhao, Rui, Michor, Franziska, Meric-Bernstam, Funda, Navin, Nicholas E
Format: Article
Language:English
Subjects:
Breast cancer
Breast Neoplasms - genetics
Care and treatment
Cell Line, Tumor
Chromosomes
Clonal Evolution
Development and progression
DNA Fingerprinting
DNA sequencing
Estrogen
Female
Genetic aspects
Genetic Variation
Genome - genetics
Genomes
Genomics
Humans
Medical research
Models, Theoretical
Mutation
Mutation - genetics
Nucleotide sequencing
Patient outcomes
Sequence Analysis, DNA
Single-Cell Analysis
Triple Negative Breast Neoplasms - genetics
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Summary: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 (
ISSN:0028-0836
1476-4687
DOI:10.1038/nature13600