NRG1 fusions in breast cancer

Abstract

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.

NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis

“…Although a recent report initially identified four cases of NRG1+ breast cancer out of 571 cases by WTS (WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1), further analysis of the RNA sequencing data identified only FAM91A1-NRG1 and ZNF704-NRG1 as truly in-frame, resulting in a true incidence of 0.35% (2/571) [45]. Furthermore, the same study identified 20 out of the first 250 (8%) breast cancer carcinoma samples to have a detectable DNA breakpoint within NRG1 but no RNA transcript was detected.…”

“…This DOC4-NRG1 fusion was generated by chromosomal translocation between 5′ fusion partner gene DOC4 and 3′ NRG1 gene that contains the EGF-like domain identical to the mechanism in generating the RTK fusions [1,2]. In-depth whole transcriptome sequencing (WTS) in 2021 indicated that the DOC-NRG1 fusion variant harbored a more complex rearrangement as PPP6R3-TENM4-NRG1 (PPP6R3-DOC4-NRG1) [45]. In 2003, the chromosomal breakpoints spreading over 1.1 Mb of NRG1 were identified in four additional breast cancer cell lines (ZR-75-1, HCC1937, SUM-52, UACC-812) and two pancreatic cancer cell lines (PaTu I and SUIT-2), providing further evidence that NRG1 breakpoints could be a recurring phenomenon in solid tumors [46].…”

“…The overall incidence of NRG1 and NRG2 fusions is very rare [5,9,10,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58]. In many tumor types, only limited numbers (or even just one) of NRG1 or NRG2 fusion variant have been identified.…”

“…In many tumor types, only limited numbers (or even just one) of NRG1 or NRG2 fusion variant have been identified. By percentage, there is no organ dominance of the presence of NRG1 or NRG2 fusions [5,9,10,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] in contrast to another rare RTK fusion, tropomyosin receptor kinase (TRK), encoded by the neurotrophic receptor tyrosine kinase gene (NRTK), where it is concentrated in certain pediatric and adult tumors [59]. The incidence of NRG2α fusions are even rarer and are five to ten times lower in frequency then NRG1 fusions [9,10,55] (Box 1).…”

Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer

“…This theory encourages more research in the signal pathway to determine if not only inhibition of this pathway but maybe agonism can lead to tumor regression. Whether or not this is the explanation, because many NRG1 rearrangements seem to be inactivating, the correct identification of activating fusions may require care [24].…”