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Contributed by Martin M. Matzuk, January 30, 2015 (sent for review December 22, 2014; reviewed by Stephen Hillier and Barbara Vanderhyden)
Significance
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer and is typically detected only at advanced stages due to lack of effective early screening tools. Fusion genes are among the most cancer-specific signatures known and, when highly recurrent, they have the potential to serve as screening tools. Here we identified BCAM-AKT2 as a cancer-specific fusion gene present in 7% of HGSC tumors, a significant frequency in this highly heterogeneous disease. This fusion results in an aberrant kinase whose constant activity contributes to cancer formation. Thus, the BCAM-AKT2 fusion gene could be important for understanding and identifying clinically relevant subtypes of HGSC, and could be a novel therapeutic target for developing small-molecule drugs.
Abstract
High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient’s tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.
Footnotes
↵1K.K. and C.C. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: mmatzuk{at}bcm.edu or yen{at}bcm.edu.
Author contributions: K.K. and L.Y. designed research; K.K., P.-W.C., L.L., Y.W., and A.E.B. performed research; S.M.H. and M.M.M. contributed new reagents/analytic tools; K.K., C.C., A.M., and L.Y. analyzed data; and K.K., M.M.M., and L.Y. wrote the paper.
Reviewers: S.H., The University of Edinburgh; and B.V., University of Ottawa.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1501735112/-/DCSupplemental.
BCAM-AKT2 fusion in high-grade serous cancer
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