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Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma
- Source :
- Proceedings of the National Academy of Sciences. 112
- Publication Year :
- 2015
- Publisher :
- Proceedings of the National Academy of Sciences, 2015.
-
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.
- Subjects :
- Oncogene Proteins, Fusion
Molecular Sequence Data
AKT2
Carcinoma, Ovarian Epithelial
Biology
Transfection
Translocation, Genetic
Fusion gene
BCAM
Cell Line, Tumor
medicine
Chromosomes, Human
Humans
Amino Acid Sequence
Neoplasms, Glandular and Epithelial
RNA, Messenger
Phosphorylation
Gene Rearrangement
Ovarian Neoplasms
Multidisciplinary
Base Sequence
Kinase
Cell Membrane
Cancer
Gene rearrangement
medicine.disease
Fusion protein
Cystadenocarcinoma, Serous
Enzyme Activation
Gene Expression Regulation, Neoplastic
PNAS Plus
Protein Biosynthesis
embryonic structures
Cancer research
Female
CRISPR-Cas Systems
Neoplasm Grading
Proto-Oncogene Proteins c-akt
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....90b8a69a72cbea4253212d41064b1366