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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-90170-1 |
| _version_ | 1819200408475664384 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T03:31:45Z |
| format | Article |
| id | doaj.art-999832948d3245a391877d69ab0c3083 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T03:31:45Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-999832948d3245a391877d69ab0c30832022-12-21T18:01:40ZengNature PortfolioScientific Reports2045-23222021-05-0111111210.1038/s41598-021-90170-1Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneityTanya N. Phung0Timothy H. Webster1Elizabeth Lenkiewicz2Smriti Malasi3Mariacarla Andreozzi4Ann E. McCullough5Karen S. Anderson6Barbara A. Pockaj7Melissa A. Wilson8Michael T. Barrett9School of Life Sciences, Arizona State UniversitySchool of Life Sciences, Arizona State UniversityDivision of Hematology/Oncology, Department of Internal Medicine, Mayo ClinicDivision of Hematology/Oncology, Department of Internal Medicine, Mayo ClinicDivision of Hematology/Oncology, Department of Internal Medicine, Mayo ClinicDepartment of Pathology and Laboratory Medicine, Mayo Clinic in ArizonaBiodesign Institute, Arizona State UniversityDivision of General Surgery, Section of Surgical Oncology, Mayo Clinic in ArizonaSchool of Life Sciences, Arizona State UniversityDivision of Hematology/Oncology, Department of Internal Medicine, Mayo ClinicAbstract 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.https://doi.org/10.1038/s41598-021-90170-1 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-021-90170-1 |
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