Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing

Anna K. Casasent; Aislyn Schalck; Ruli Gao; Emi Sei; Annalyssa Long; William Pangburn; Tod Casasent; Funda Meric-Bernstam; Mary E. Edgerton; Nicholas E. Navin

doi:10.1016/j.cell.2017.12.007

Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing

Anna K. Casasent, Aislyn Schalck, Ruli Gao, Emi Sei, Annalyssa Long, William Pangburn, Tod Casasent, Funda Meric-Bernstam, Mary E. Edgerton^*, Nicholas E. Navin

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

308 Scopus citations

Abstract

Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas. Retaining spatial information in single-cell analysis provides insight into clonal invasion patterns and disease progression in patients with DCIS-IDC breast cancer.

Original language	English (US)
Pages (from-to)	205-217.e12
Journal	Cell
Volume	172
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2017.12.007
State	Published - Jan 11 2018

Funding

This work was supported by grants to N.E.N. from the Lefkofsky Family Foundation, NCI (CA169244), American Cancer Society (129098-RSG-16-092-01-TBG), and Chan-Zuckerberg Initiative (HCA-A-1704-01668). N.E.N. is a T.C. Hsu Endowed Scholar, AAAS Wachtel Scholar, Andrew Sabin Family Fellow, and Jack & Beverly Randall Innovator. A.K.C. is supported by a Rosalie B. Hite Fellowship in Cancer Research. A.L. and W.P. were supported by Cancer Prevention and Research Institute of Texas (RP140103). This work was also supported by the MD Anderson Sequencing and Microarray Core Facility (CA016672). We thank Hank Adams, Louis Ramagli, Erika Thompson, Hongli Tang, Alexander Davis, and Jake Leighton for their help. We are also grateful to Sohrab Shah and his group for support using the TimeScape software. This work was supported by grants to N.E.N. from the Lefkofsky Family Foundation , NCI ( CA169244 ), American Cancer Society ( 129098-RSG-16-092-01-TBG ), and Chan-Zuckerberg Initiative ( HCA-A-1704-01668 ). N.E.N. is a T.C. Hsu Endowed Scholar, AAAS Wachtel Scholar, Andrew Sabin Family Fellow, and Jack & Beverly Randall Innovator. A.K.C. is supported by a Rosalie B. Hite Fellowship in Cancer Research . A.L. and W.P. were supported by Cancer Prevention and Research Institute of Texas ( RP140103 ). This work was also supported by the MD Anderson Sequencing and Microarray Core Facility ( CA016672 ). We thank Hank Adams, Louis Ramagli, Erika Thompson, Hongli Tang, Alexander Davis, and Jake Leighton for their help. We are also grateful to Sohrab Shah and his group for support using the TimeScape software.

Keywords

breast cancer
breast cancer progression
cancer genomics
clonal evolution
copy number evolution
ductal carcinoma in situ
genome evolution
intratumor heterogeneity
invasion
single-cell sequencing

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2017.12.007

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title = "Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing",

abstract = "Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas. Retaining spatial information in single-cell analysis provides insight into clonal invasion patterns and disease progression in patients with DCIS-IDC breast cancer.",

keywords = "breast cancer, breast cancer progression, cancer genomics, clonal evolution, copy number evolution, ductal carcinoma in situ, genome evolution, intratumor heterogeneity, invasion, single-cell sequencing",

author = "Casasent, {Anna K.} and Aislyn Schalck and Ruli Gao and Emi Sei and Annalyssa Long and William Pangburn and Tod Casasent and Funda Meric-Bernstam and Edgerton, {Mary E.} and Navin, {Nicholas E.}",

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AU - Pangburn, William

AU - Casasent, Tod

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AU - Navin, Nicholas E.

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N2 - Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas. Retaining spatial information in single-cell analysis provides insight into clonal invasion patterns and disease progression in patients with DCIS-IDC breast cancer.

AB - Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas. Retaining spatial information in single-cell analysis provides insight into clonal invasion patterns and disease progression in patients with DCIS-IDC breast cancer.

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Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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