دورية أكاديمية
NRG1 fusions in breast cancer.
| العنوان: | NRG1 fusions in breast cancer. |
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| المؤلفون: | Howarth KD; Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK. karen.howarth@inivata.com.; Department of Pathology, University of Cambridge, Cambridge, UK. karen.howarth@inivata.com.; Present addresses: Inivata Ltd, Babraham Research Park, Cambridge, CB22 3FH, UK. karen.howarth@inivata.com., Mirza T; Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK.; Department of Pathology, University of Cambridge, Cambridge, UK.; Present addresses: Francis Crick Institute, Midland Road, London, NW1 1AT, UK., Cooke SL; Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK.; Department of Pathology, University of Cambridge, Cambridge, UK.; Present addresses: Wolfson Wohl Cancer Research Centre, Garscube Estate, Bearsden, G61 1QH, UK., Chin SF; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK., Pole JC; Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK.; Department of Pathology, University of Cambridge, Cambridge, UK.; Present addresses: Illumina Cambridge, Granta Park, Great Abington, Cambridge, CB21 6GP, UK., Turro E; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.; Present addresses: Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Eldridge MD; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK., Garcia RM; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK., Rueda OM; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK.; Present addresses: MRC Biostatistics Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK., Boursnell C; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK., Abraham JE; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK.; Cambridge Breast Cancer Research Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 2QQ, UK., Caldas C; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK.; Cambridge Breast Cancer Research Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 2QQ, UK., Edwards PAW; Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK. pawe1@cam.ac.uk.; Department of Pathology, University of Cambridge, Cambridge, UK. pawe1@cam.ac.uk.; Department of Oncology, Cancer Research UK Cambridge Institute and Cancer Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, UK. pawe1@cam.ac.uk. |
| المصدر: | Breast cancer research : BCR [Breast Cancer Res] 2021 Jan 07; Vol. 23 (1), pp. 3. Date of Electronic Publication: 2021 Jan 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London, UK : BioMed Central Ltd Original Publication: London, UK : Current Science, c1999- |
| مواضيع طبية MeSH: | Biomarkers, Tumor*, Breast Neoplasms/*genetics , Neuregulin-1/*genetics , Oncogene Proteins, Fusion/*genetics, Alternative Splicing ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Gene Rearrangement ; Genetic Loci ; Humans ; Neuregulin-1/chemistry ; Neuregulin-1/metabolism ; Oncogene Proteins, Fusion/metabolism ; Signal Transduction ; Translocation, Genetic |
| مستخلص: | 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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| معلومات مُعتمدة: | 29567 United Kingdom CRUK_ Cancer Research UK; 14545 United Kingdom CRUK_ Cancer Research UK; C1023/A14545 United Kingdom CRUK_ Cancer Research UK; MC_UU_00002/16 United Kingdom MRC_ Medical Research Council; A16942 United Kingdom CRUK_ Cancer Research UK; A27657 United Kingdom CRUK_ Cancer Research UK |
| فهرسة مساهمة: | Keywords: Breast cancer; Clinically actionable; MDA-MB-175; NRG1; NRG1 fusions; Transcriptome sequencing; Whole-genome sequencing |
| المشرفين على المادة: | 0 (Biomarkers, Tumor) 0 (NRG1 protein, human) 0 (Neuregulin-1) 0 (Oncogene Proteins, Fusion) |
| تواريخ الأحداث: | Date Created: 20210108 Date Completed: 20220106 Latest Revision: 20240330 |
| رمز التحديث: | 20240330 |
| مُعرف محوري في PubMed: | PMC7788813 |
| DOI: | 10.1186/s13058-020-01377-5 |
| PMID: | 33413557 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1465-542X |
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| DOI: | 10.1186/s13058-020-01377-5 |