scholarly journals Gene Fusions Associated with Recurrent Amplicons Represent a Class of Passenger Aberrations in Breast Cancer

Neoplasia ◽  
2012 ◽  
Vol 14 (8) ◽  
pp. 702-IN13 ◽  
Author(s):  
Shanker Kalyana-Sundaram ◽  
Sunita Shankar ◽  
Scott DeRoo ◽  
Matthew K. Iyer ◽  
Nallasivam Palanisamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Fusions

scholarly journals NRG1 fusions in breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Karen D. Howarth ◽  
Tashfina Mirza ◽  
Susanna L. Cooke ◽  
Suet-Feung Chin ◽  
Jessica C. Pole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Cancer Cell Line ◽  
Cytoplasmic Tail ◽  
Gene Fusions ◽  
Breast Cancers ◽  
Autocrine Loop ◽  
Multiple Transcripts ◽  
Autocrine Stimulation

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.

scholarly journals Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Li Li ◽  
Ling Lin ◽  
Jamunarani Veeraraghavan ◽  
Yiheng Hu ◽  
Xian Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Gene Fusions ◽  
Therapeutic Role

scholarly journals O43: CLINICAL IMPACT OF GENE FUSIONS IN BREAST CANCER BRAIN METASTASES

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
N Cosgrove ◽  
D Vareslija ◽  
SJ Furney ◽  
S Oesterreich ◽  
AV Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Significant Role ◽  
Mitogen Activated Protein Kinase ◽  
Parp Inhibition ◽  
Gene Fusions ◽  
Genomic Alterations ◽  
Breast Tumours ◽  
Breast Cancer Brain Metastases

Abstract Introduction The incidence of brain metastases is increasing despite longer survival rates for patients with advanced breast cancer. The identification of novel therapeutic targets for these patients is an urgent unmet clinical need. Sequencing of metastatic tumours have largely focused on mutations however gene fusions have an important, yet underappreciated role in tumorigenesis and disease progression. In this study, we investigate the role of gene fusions in brain metastatic disease and their impact on altered therapeutic responses. Method RNA sequencing was performed on the largest reported cohort of patient matched primary and resected brain metastatic tumours (45 patients n=90 samples). Expressed gene fusions were detected computationally using STAR-Fusion and Arriba. Result We identified differential gene fusion burden in brain metastatic tumours (medium of 58) vs. primary breast tumours (medium of 38) (p < 0.05). Enrichment for fusions in pathways associated with tumour cell plasticity and proliferation with recurrent fusions in known cancer driver genes related to MAPK, HER signaling identified. Of note, a fusion in CDK12 is of clinical importance. Increased genomic alterations and over expression of CDK12 is associated with brain metastases free survival in an independent cohort of primary breast tumours with a recorded history of brain metastases. It has been proposed that inhibition of CDK12 may induce BRCAness in tumours making them sensitive to PARP inhibition. Conclusion These results highlight the significant role of gene fusions in breast cancer brain metastases. Abbreviations MAPK Mitogen Activated Protein Kinase, HER Human Epidermal Receptor, CDK12 Cyclin Dependent Kinase 12 Take-home message We highlight the significant role of gene fusions in breast cancer brain metastases and offer specific actionable genomic alterations to be exploited.

Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer

2017 ◽  
Vol 8 (3) ◽  
pp. 336-353 ◽  
Author(s):  
Karina J. Matissek ◽  
Maristela L. Onozato ◽  
Sheng Sun ◽  
Zongli Zheng ◽  
Andrew Schultz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Gene Fusions ◽  
Hormone Receptor Positive ◽  
Poor Outcomes ◽  
Positive Breast Cancer

Abstract 5468: Gene fusions in breast cancer in Nigerian women

2020 ◽  
Author(s):  
Anna Elizabeth Woodard ◽  
Toshio F. Yoshimatsu ◽  
Jason J. Pitt ◽  
Yonglan Zheng ◽  
Olufunmilayo I. Olopade ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Fusions ◽  
Nigerian Women

scholarly journals Landscape analysis of adjacent gene rearrangements reveals BCL2L14–ETV6 gene fusions in more aggressive triple-negative breast cancer

2020 ◽  
Vol 117 (18) ◽  
pp. 9912-9921
Author(s):  
Sanghoon Lee ◽  
Yiheng Hu ◽  
Suet Kee Loo ◽  
Ying Tan ◽  
Rohit Bhargava ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ectopic Expression ◽  
Whole Genome Sequencing Data ◽  
Gene Rearrangements ◽  
Gene Fusions ◽  
Adjacent Gene ◽  
Mesenchymal Transition ◽  
Recurrent Gene Fusions

Triple-negative breast cancer (TNBC) accounts for 10 to 20% of breast cancer, with chemotherapy as its mainstay of treatment due to lack of well-defined targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations. Recurrent gene fusions comprise a class of viable genetic targets in solid tumors; however, their role in breast cancer remains underappreciated due to the complexity of genomic rearrangements in this cancer. Our interrogation of the whole-genome sequencing data for 215 breast tumors catalogued 99 recurrent gene fusions, 57% of which are cryptic adjacent gene rearrangements (AGRs). The most frequent AGRs, BCL2L14–ETV6, TTC6–MIPOL1, ESR1–CCDC170, and AKAP8–BRD4, were preferentially found in the more aggressive forms of breast cancers that lack well-defined genetic targets. Among these, BCL2L14–ETV6 was exclusively detected in TNBC, and interrogation of four independent patient cohorts detected BCL2L14–ETV6 in 4.4 to 12.2% of TNBC tumors. Interestingly, these fusion-positive tumors exhibit more aggressive histopathological features, such as gross necrosis and high tumor grade. Amid TNBC subtypes, BCL2L14–ETV6 is most frequently detected in the mesenchymal entity, accounting for ∼19% of these tumors. Ectopic expression of BCL2L14–ETV6 fusions induce distinct expression changes from wild-type ETV6 and enhance cell motility and invasiveness of TNBC and benign breast epithelial cells. Furthermore, BCL2L14–ETV6 fusions prime partial epithelial–mesenchymal transition and endow resistance to paclitaxel treatment. Together, these data reveal AGRs as a class of underexplored genetic aberrations that could be pathological in breast cancer, and identify BCL2L14–ETV6 as a recurrent gene fusion in more aggressive form of TNBC tumors.

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