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NRG1 fusions in breast cancer

BACKGROUND: NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocr...

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Autores principales: Howarth, Karen D., Mirza, Tashfina, Cooke, Susanna L., Chin, Suet-Feung, Pole, Jessica C., Turro, Ernest, Eldridge, Matthew D., Garcia, Raquel Manzano, Rueda, Oscar M., Boursnell, Chris, Abraham, Jean E., Caldas, Carlos, Edwards, Paul A. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788813/
https://www.ncbi.nlm.nih.gov/pubmed/33413557
http://dx.doi.org/10.1186/s13058-020-01377-5
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author Howarth, Karen D.
Mirza, Tashfina
Cooke, Susanna L.
Chin, Suet-Feung
Pole, Jessica C.
Turro, Ernest
Eldridge, Matthew D.
Garcia, Raquel Manzano
Rueda, Oscar M.
Boursnell, Chris
Abraham, Jean E.
Caldas, Carlos
Edwards, Paul A. W.
author_facet Howarth, Karen D.
Mirza, Tashfina
Cooke, Susanna L.
Chin, Suet-Feung
Pole, Jessica C.
Turro, Ernest
Eldridge, Matthew D.
Garcia, Raquel Manzano
Rueda, Oscar M.
Boursnell, Chris
Abraham, Jean E.
Caldas, Carlos
Edwards, Paul A. W.
author_sort Howarth, Karen D.
collection PubMed
description BACKGROUND: NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer. METHODS: We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers. RESULTS: We found that the MDA-MB-175 fusion—originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1—is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers. CONCLUSIONS: Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management.
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spelling pubmed-77888132021-01-07 NRG1 fusions in breast cancer Howarth, Karen D. Mirza, Tashfina Cooke, Susanna L. Chin, Suet-Feung Pole, Jessica C. Turro, Ernest Eldridge, Matthew D. Garcia, Raquel Manzano Rueda, Oscar M. Boursnell, Chris Abraham, Jean E. Caldas, Carlos Edwards, Paul A. W. Breast Cancer Res Research Article BACKGROUND: NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer. METHODS: We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers. RESULTS: We found that the MDA-MB-175 fusion—originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1—is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers. CONCLUSIONS: Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management. BioMed Central 2021-01-07 2021 /pmc/articles/PMC7788813/ /pubmed/33413557 http://dx.doi.org/10.1186/s13058-020-01377-5 Text en © The Author(s) 2021 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
spellingShingle Research Article
Howarth, Karen D.
Mirza, Tashfina
Cooke, Susanna L.
Chin, Suet-Feung
Pole, Jessica C.
Turro, Ernest
Eldridge, Matthew D.
Garcia, Raquel Manzano
Rueda, Oscar M.
Boursnell, Chris
Abraham, Jean E.
Caldas, Carlos
Edwards, Paul A. W.
NRG1 fusions in breast cancer
title NRG1 fusions in breast cancer
title_full NRG1 fusions in breast cancer
title_fullStr NRG1 fusions in breast cancer
title_full_unstemmed NRG1 fusions in breast cancer
title_short NRG1 fusions in breast cancer
title_sort nrg1 fusions in breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788813/
https://www.ncbi.nlm.nih.gov/pubmed/33413557
http://dx.doi.org/10.1186/s13058-020-01377-5
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