Breast tumours maintain a reservoir of subclonal diversity during expansion

Darlan C. Minussi; Michael D. Nicholson; Hanghui Ye; Alexander Davis; Kaile Wang; Toby Baker; Maxime Tarabichi; Emi Sei; Haowei Du; Mashiat Rabbani; Cheng Peng; Min Hu; Shanshan Bai; Yu wei Lin; Aislyn Schalck; Asha Multani; Jin Ma; Thomas O. McDonald; Anna Casasent; Angelica Barrera; Hui Chen; Bora Lim; Banu Arun; Funda Meric-Bernstam; Peter Van Loo; Franziska Michor; Nicholas E. Navin

doi:10.1038/s41586-021-03357-x

Breast tumours maintain a reservoir of subclonal diversity during expansion

Darlan C. Minussi, Michael D. Nicholson, Hanghui Ye, Alexander Davis, Kaile Wang, Toby Baker, Maxime Tarabichi, Emi Sei, Haowei Du, Mashiat Rabbani, Cheng Peng, Min Hu, Shanshan Bai, Yu wei Lin, Aislyn Schalck, Asha Multani, Jin Ma, Thomas O. McDonald, Anna Casasent, Angelica BarreraHui Chen, Bora Lim, Banu Arun, Funda Meric-Bernstam, Peter Van Loo, Franziska Michor, Nicholas E. Navin

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98 Scopus citations

Abstract

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited^1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

Original language	English (US)
Pages (from-to)	302-308
Number of pages	7
Journal	Nature
Volume	592
Issue number	7853
DOIs	https://doi.org/10.1038/s41586-021-03357-x
State	Published - Apr 8 2021

ASJC Scopus subject areas

General

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Tissue Biospecimen and Pathology Resource
SINGLE Core
Cytogenetics and Cell Authentication Core
Clinical and Translational Research Center

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Minussi, D. C., Nicholson, M. D., Ye, H., Davis, A., Wang, K., Baker, T., Tarabichi, M., Sei, E., Du, H., Rabbani, M., Peng, C., Hu, M., Bai, S., Lin, Y. W., Schalck, A., Multani, A., Ma, J., McDonald, T. O., Casasent, A., ... Navin, N. E. (2021). Breast tumours maintain a reservoir of subclonal diversity during expansion. Nature, 592(7853), 302-308. https://doi.org/10.1038/s41586-021-03357-x

Minussi, DC, Nicholson, MD, Ye, H, Davis, A, Wang, K, Baker, T, Tarabichi, M, Sei, E, Du, H, Rabbani, M, Peng, C, Hu, M, Bai, S, Lin, YW, Schalck, A, Multani, A, Ma, J, McDonald, TO, Casasent, A, Barrera, A, Chen, H , Lim, B , Arun, B , Meric-Bernstam, F , Van Loo, P, Michor, F & Navin, NE 2021, 'Breast tumours maintain a reservoir of subclonal diversity during expansion', Nature, vol. 592, no. 7853, pp. 302-308. https://doi.org/10.1038/s41586-021-03357-x

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title = "Breast tumours maintain a reservoir of subclonal diversity during expansion",

abstract = "Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.",

author = "Minussi, {Darlan C.} and Nicholson, {Michael D.} and Hanghui Ye and Alexander Davis and Kaile Wang and Toby Baker and Maxime Tarabichi and Emi Sei and Haowei Du and Mashiat Rabbani and Cheng Peng and Min Hu and Shanshan Bai and Lin, {Yu wei} and Aislyn Schalck and Asha Multani and Jin Ma and McDonald, {Thomas O.} and Anna Casasent and Angelica Barrera and Hui Chen and Bora Lim and Banu Arun and Funda Meric-Bernstam and {Van Loo}, Peter and Franziska Michor and Navin, {Nicholas E.}",

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T1 - Breast tumours maintain a reservoir of subclonal diversity during expansion

AU - Minussi, Darlan C.

AU - Nicholson, Michael D.

AU - Ye, Hanghui

AU - Davis, Alexander

AU - Wang, Kaile

AU - Baker, Toby

AU - Tarabichi, Maxime

AU - Sei, Emi

AU - Du, Haowei

AU - Rabbani, Mashiat

AU - Peng, Cheng

AU - Hu, Min

AU - Bai, Shanshan

AU - Lin, Yu wei

AU - Schalck, Aislyn

AU - Multani, Asha

AU - Ma, Jin

AU - McDonald, Thomas O.

AU - Casasent, Anna

AU - Barrera, Angelica

AU - Chen, Hui

AU - Lim, Bora

AU - Arun, Banu

AU - Meric-Bernstam, Funda

AU - Van Loo, Peter

AU - Michor, Franziska

AU - Navin, Nicholas E.

PY - 2021/4/8

Y1 - 2021/4/8

N2 - Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

AB - Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

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Breast tumours maintain a reservoir of subclonal diversity during expansion

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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