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Updated: Mar 20, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other
Timothy M Shaver1, Brian D Lehmann2, J Scott Beeler1
1Department of Biochemistry, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract:
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850-60. ©2016 AACR.
Insights
Researchers identified novel gene fusions in triple-negative breast cancer (TNBC) and other cancers using a new prediction method. This discovery highlights the importance of detecting gene rearrangements for targeted cancer therapies.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Triple-negative breast cancer (TNBC) and other heterogeneous malignancies pose clinical challenges due to a lack of actionable driver alterations.
- Genomic instability in these cancers leads to chromosomal rearrangements affecting gene structure and expression, which are difficult to identify.
- Current methods for detecting gene rearrangements are technically challenging, limiting therapeutic intervention strategies.
Purpose of the Study:
- To develop and apply a novel quantitative approach for predicting gene rearrangements in tumor-derived genetic material.
- To identify and characterize novel oncogenic gene fusions in TNBC and other cancers.
- To assess the clinical relevance of identified gene fusions for targeted therapy.
Main Methods:
- Development of a new computational approach for quantitative prediction of gene rearrangements.
- Application of the method to tumor-derived genetic material.
- Characterization of identified gene fusions, including novel oncogenic fusions and known hybrid transcripts.
Main Results:
- Identification and characterization of a novel oncogenic MERTK fusion.
- Discovery of the targetable FGFR3-TACC3 fusion in TNBC, including a clinical occurrence and cell line model.
- Identification of a wide range of novel and known hybrid transcripts across various malignancies, including rearrangements involving noncoding regions and genes like ALK, CSF1R, and CD274/PD-L1.
- Over 1,000 genetic alterations were identified, emphasizing the significance of noncoding gene rearrangement partners.
Conclusions:
- The study identified numerous genetic alterations, including novel and targetable gene fusions in TNBC.
- Considering noncoding gene rearrangement partners is crucial for a comprehensive understanding of cancer genomics.
- Advancing gene fusion detection methods is essential for developing targeted therapies for molecularly heterogeneous cancers.
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