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NRG1 fusions in breast cancer
- Source :
- Breast Cancer Research : BCR, Breast Cancer Research, Vol 23, Iss 1, Pp 1-12 (2021)
- Publication Year :
- 2021
- Publisher :
- BioMed Central, 2021.
-
Abstract
- Funder: Cancer Research UK<br />Funder: Breast Cancer Now<br />Funder: Addenbrookes Charitable Trust<br />Funder: Mark Foundation For Cancer Research; doi: http://dx.doi.org/10.13039/100014599<br />Funder: Addenbrooke's Charitable Trust, Cambridge University Hospitals (GB)<br />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.
- Subjects :
- MDA-MB-175
Oncogene Proteins, Fusion
Neuregulin-1
Breast Neoplasms
Biology
lcsh:RC254-282
Clinically actionable
Translocation, Genetic
Receptor tyrosine kinase
03 medical and health sciences
Exon
0302 clinical medicine
Breast cancer
Cell Line, Tumor
mental disorders
Biomarkers, Tumor
medicine
Humans
Transcriptome sequencing
Autocrine signalling
Gene
030304 developmental biology
NRG1 fusions
Gene Rearrangement
Whole genome sequencing
0303 health sciences
NRG1
Whole-genome sequencing
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Gene Expression Regulation, Neoplastic
Alternative Splicing
Genetic Loci
030220 oncology & carcinogenesis
RNA splicing
Cancer research
biology.protein
Female
Tyrosine kinase
Signal Transduction
Research Article
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research : BCR, Breast Cancer Research, Vol 23, Iss 1, Pp 1-12 (2021)
- Accession number :
- edsair.doi.dedup.....1ea822c2084c8f10db30b128adcae9ab