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Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification
BACKGROUND: HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440518/ https://www.ncbi.nlm.nih.gov/pubmed/25994018 http://dx.doi.org/10.1186/s13059-015-0657-6 |
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author | Ng, Charlotte KY Martelotto, Luciano G Gauthier, Arnaud Wen, Huei-Chi Piscuoglio, Salvatore Lim, Raymond S Cowell, Catherine F Wilkerson, Paul M Wai, Patty Rodrigues, Daniel N Arnould, Laurent Geyer, Felipe C Bromberg, Silvio E Lacroix-Triki, Magali Penault-Llorca, Frederique Giard, Sylvia Sastre-Garau, Xavier Natrajan, Rachael Norton, Larry Cottu, Paul H Weigelt, Britta Vincent-Salomon, Anne Reis-Filho, Jorge S |
author_facet | Ng, Charlotte KY Martelotto, Luciano G Gauthier, Arnaud Wen, Huei-Chi Piscuoglio, Salvatore Lim, Raymond S Cowell, Catherine F Wilkerson, Paul M Wai, Patty Rodrigues, Daniel N Arnould, Laurent Geyer, Felipe C Bromberg, Silvio E Lacroix-Triki, Magali Penault-Llorca, Frederique Giard, Sylvia Sastre-Garau, Xavier Natrajan, Rachael Norton, Larry Cottu, Paul H Weigelt, Britta Vincent-Salomon, Anne Reis-Filho, Jorge S |
author_sort | Ng, Charlotte KY |
collection | PubMed |
description | BACKGROUND: HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases. RESULTS: We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers. CONCLUSIONS: Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0657-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4440518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-44405182015-05-22 Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification Ng, Charlotte KY Martelotto, Luciano G Gauthier, Arnaud Wen, Huei-Chi Piscuoglio, Salvatore Lim, Raymond S Cowell, Catherine F Wilkerson, Paul M Wai, Patty Rodrigues, Daniel N Arnould, Laurent Geyer, Felipe C Bromberg, Silvio E Lacroix-Triki, Magali Penault-Llorca, Frederique Giard, Sylvia Sastre-Garau, Xavier Natrajan, Rachael Norton, Larry Cottu, Paul H Weigelt, Britta Vincent-Salomon, Anne Reis-Filho, Jorge S Genome Biol Research BACKGROUND: HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases. RESULTS: We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers. CONCLUSIONS: Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0657-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-05-22 2015 /pmc/articles/PMC4440518/ /pubmed/25994018 http://dx.doi.org/10.1186/s13059-015-0657-6 Text en © Ng et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ng, Charlotte KY Martelotto, Luciano G Gauthier, Arnaud Wen, Huei-Chi Piscuoglio, Salvatore Lim, Raymond S Cowell, Catherine F Wilkerson, Paul M Wai, Patty Rodrigues, Daniel N Arnould, Laurent Geyer, Felipe C Bromberg, Silvio E Lacroix-Triki, Magali Penault-Llorca, Frederique Giard, Sylvia Sastre-Garau, Xavier Natrajan, Rachael Norton, Larry Cottu, Paul H Weigelt, Britta Vincent-Salomon, Anne Reis-Filho, Jorge S Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title | Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title_full | Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title_fullStr | Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title_full_unstemmed | Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title_short | Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification |
title_sort | intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous her2 gene amplification |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440518/ https://www.ncbi.nlm.nih.gov/pubmed/25994018 http://dx.doi.org/10.1186/s13059-015-0657-6 |
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