Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Proceedings of the National Academy of Sciences of the United States of America
Kalpana KannanLaising Yen

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...Continue Reading

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Citations

Feb 19, 2016·British Journal of Cancer·Kosuke HiramatsuTadashi Kimura
Apr 8, 2015·Molecular Medicine Reports·Haiyan JiangLei Qi
Mar 31, 2015·International Journal of Molecular Medicine·Haiyan JiangQinghua Xi
Dec 19, 2015·Oxidative Medicine and Cellular Longevity·Aida Barreiro-AlonsoM Esperanza Cerdán
Oct 16, 2015·Journal of Clinical Pathology·Yun GuJiandong Wang
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Dec 27, 2017·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Jeremy Chien, Geeta Mehta
Feb 20, 2018·Molecular Cancer·Haim WernerIlan Bruchim
Aug 2, 2020·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Ying-Hsia ChuPeter M Sadow
Feb 2, 2019·Scientific Reports·Yan-Ping YuJian-Hua Luo
Sep 1, 2021·Journal of Medical Genetics·Yi Zhou, Mona El-Bahrawy

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