Discovery of Fusion Genes in Breast Cancer

Institution: Stanford University
Investigator(s): Jonathan Pollack, M.D., Ph.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15IB-0123 Award: $160,000
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2009)

Chromosome rearrangements resulting in the expression of fusions or chimeras between two different genes is a common mechanism for activation of cancer genes in blood cancers, where the fusion gene contributes to cancer development but is also a useful biomarker for diagnosis and target for therapy. While common in blood cancers, fusion genes have been considered rare in solid tumors like breast cancer. The discovery of fusion genes in breast cancer would provide a new foothold to study and understand the pathogenesis of this disease, as well as new opportunities for diagnosis and therapy. Fusion genes were discovered in prostate cancer only three years ago and already that knowledge is being translated towards improved diagnosis and therapy. A similar impact would be expected in breast cancer.

We recently developed and validated the feasibility of a novel microarray-based approach for discovery of fusion genes. The approach is based on detecting transcribed exonic breakpoints and fusion junction sequences. The goals for this project include, (1) design and validation of a custom screening array to detect gene fusions; (2) use the array to profile a collection of breast cancer cell lines and clinical specimens; (3) validation of any identified fusions by reverse-transcription polymerase chain reaction (RT-PCR), and analyzing their prevalence in a large independent set of clinical samples; and (4) functional characterization of at least one fusion gene through studies of breast epithelial cells in culture. In parallel, we will also incorporate “next-generation” DNA sequencing approaches to find fusion gene candidates.

The discovery of recurrent fusion gene(s) in breast cancer would provide a significant advance in our understanding of breast cancer pathogenesis, as well as important opportunities for improved diagnosis and therapy, much as has occurred with the recent discovery of oncogenic fusion genes in prostate cancer.




Final Report (2010)

Chromosome rearrangements resulting in the expression of fusions or chimeras between two different genes is a common mechanism for activation of cancer genes in blood cancers. Such fusion genes have also become useful biomarkers for diagnosis and targets for therapy. While common in blood cancers, fusion genes have been considered rare in solid tumors. However, the serendipitous discovery of fusion genes in prostate cancer suggested the possibility that fusion genes might also exist in other solid tumors like breast cancer, but have so far eluded detection.

The goal of our study was to develop and apply genomics technology to discover fusion genes in breast cancer. While we pursued several approaches in parallel, the most productive has been next-generation (i.e. ultra-high capacity) DNA sequencing of expressed genes, where fusion genes are identifiable as chimeric sequences originating from two different genes. Analyzing 36 breast cancer cell lines, we identified and verified several fusion genes. Some of these fusions were present in more than one sample, implying that they are non-random events and possible “drivers” of breast cancer development. The known functions of the genes implicate a novel role of altered chromosome-protein dynamics in breast cancer. Studies have been initiated to further characterize the function of fusion genes.

Our goal to leverage genomics technology to discover fusion genes in breast cancer has been highly successful. Future efforts will focus on surveying additional breast cancers to discovery more fusion genes, and on characterizing the function and clinical impact of discovered fusions.