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Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer

Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than t...

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Autores principales: Magbanua, Mark Jesus M., Rugo, Hope S., Hauranieh, Louai, Roy, Ritu, Scott, Janet H., Lee, Jen Chieh, Hsiao, Feng, Sosa, Eduardo V., van’t Veer, Laura, Esserman, Laura J., Park, John W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125436/
https://www.ncbi.nlm.nih.gov/pubmed/30211312
http://dx.doi.org/10.1038/s41523-018-0083-5
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author Magbanua, Mark Jesus M.
Rugo, Hope S.
Hauranieh, Louai
Roy, Ritu
Scott, Janet H.
Lee, Jen Chieh
Hsiao, Feng
Sosa, Eduardo V.
van’t Veer, Laura
Esserman, Laura J.
Park, John W.
author_facet Magbanua, Mark Jesus M.
Rugo, Hope S.
Hauranieh, Louai
Roy, Ritu
Scott, Janet H.
Lee, Jen Chieh
Hsiao, Feng
Sosa, Eduardo V.
van’t Veer, Laura
Esserman, Laura J.
Park, John W.
author_sort Magbanua, Mark Jesus M.
collection PubMed
description Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.
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spelling pubmed-61254362018-09-12 Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer Magbanua, Mark Jesus M. Rugo, Hope S. Hauranieh, Louai Roy, Ritu Scott, Janet H. Lee, Jen Chieh Hsiao, Feng Sosa, Eduardo V. van’t Veer, Laura Esserman, Laura J. Park, John W. NPJ Breast Cancer Article Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance. Nature Publishing Group UK 2018-09-05 /pmc/articles/PMC6125436/ /pubmed/30211312 http://dx.doi.org/10.1038/s41523-018-0083-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Magbanua, Mark Jesus M.
Rugo, Hope S.
Hauranieh, Louai
Roy, Ritu
Scott, Janet H.
Lee, Jen Chieh
Hsiao, Feng
Sosa, Eduardo V.
van’t Veer, Laura
Esserman, Laura J.
Park, John W.
Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title_full Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title_fullStr Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title_full_unstemmed Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title_short Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
title_sort genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125436/
https://www.ncbi.nlm.nih.gov/pubmed/30211312
http://dx.doi.org/10.1038/s41523-018-0083-5
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