Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity

Abstract Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defin...

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Autores principales:	Tanya N. Phung, Timothy H. Webster, Elizabeth Lenkiewicz, Smriti Malasi, Mariacarla Andreozzi, Ann E. McCullough, Karen S. Anderson, Barbara A. Pockaj, Melissa A. Wilson, Michael T. Barrett
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/999832948d3245a391877d69ab0c3083
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spelling	oai:doaj.org-article:999832948d3245a391877d69ab0c30832021-12-02T15:53:10ZUnique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity10.1038/s41598-021-90170-12045-2322https://doaj.org/article/999832948d3245a391877d69ab0c30832021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90170-1https://doaj.org/toc/2045-2322Abstract Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4–18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.Tanya N. PhungTimothy H. WebsterElizabeth LenkiewiczSmriti MalasiMariacarla AndreozziAnn E. McCulloughKaren S. AndersonBarbara A. PockajMelissa A. WilsonMichael T. BarrettNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tanya N. Phung Timothy H. Webster Elizabeth Lenkiewicz Smriti Malasi Mariacarla Andreozzi Ann E. McCullough Karen S. Anderson Barbara A. Pockaj Melissa A. Wilson Michael T. Barrett Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
description	Abstract Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4–18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.
format	article
author	Tanya N. Phung Timothy H. Webster Elizabeth Lenkiewicz Smriti Malasi Mariacarla Andreozzi Ann E. McCullough Karen S. Anderson Barbara A. Pockaj Melissa A. Wilson Michael T. Barrett
author_facet	Tanya N. Phung Timothy H. Webster Elizabeth Lenkiewicz Smriti Malasi Mariacarla Andreozzi Ann E. McCullough Karen S. Anderson Barbara A. Pockaj Melissa A. Wilson Michael T. Barrett
author_sort	Tanya N. Phung
title	Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
title_short	Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
title_full	Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
title_fullStr	Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
title_full_unstemmed	Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
title_sort	unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/999832948d3245a391877d69ab0c3083
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Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity

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