Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma.
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.
Departments of Pathology & Immunology, Molecular and Cellular Biology.
Kalpana
K
Kannan
Molecular and Cellular Biology, Dan L. Duncan Cancer Center, and.
Cristian
C
Coarfa
Departments of Pathology & Immunology, Molecular and Cellular Biology.
Pei-Wen
PW
Chao
Departments of Pathology & Immunology, Molecular and Cellular Biology.
Liming
L
Luo
Departments of Pathology & Immunology, Molecular and Cellular Biology.
Yan
Y
Wang
Departments of Pathology & Immunology.
Amy E
AE
Brinegar
Dan L. Duncan Cancer Center, and Obstetrics and Gynecology.
Shannon M
SM
Hawkins
Dan L. Duncan Cancer Center, and Molecular and Human Genetics, and.
Aleksandar
A
Milosavljevic
Departments of Pathology & Immunology, Molecular and Cellular Biology, Dan L. Duncan Cancer Center, and Molecular and Human Genetics, and Pharmacology, Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030 mmatzuk@bcm.edu yen@bcm.edu.
Martin M
MM
Matzuk
Departments of Pathology & Immunology, Molecular and Cellular Biology, Dan L. Duncan Cancer Center, and Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030 mmatzuk@bcm.edu yen@bcm.edu.
Laising
L
Yen
D000595:Amino Acid Sequence; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002877:Chromosomes, Human / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014178:Translocation, Genetic
C000598294:BCAM-AKT2 fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
AKT2; BCAM; cancer-specific fusion gene; fusion kinase; high-grade serous ovarian cancer