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

Kalpana Kannan, Cristian Coarfa, Pei Wen Chao, Liming Luo, Yan Wang, Amy E. Brinegar, Shannon Hawkins, Aleksandar Milosavljevic, Martin M. Matzuk, Laising Yen

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E1272-E1277
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number11
DOIs
StatePublished - Mar 17 2015
Externally publishedYes

Fingerprint

Gene Fusion
Phosphotransferases
Ovarian Neoplasms
Carcinoma
Neoplasms
Oncogene Fusion
Clustered Regularly Interspaced Short Palindromic Repeats
Genetic Translocation
Membranes
HEK293 Cells
Neoplasm Genes
Phosphatidylinositol 3-Kinases
Protein Kinases
Cell Line
Therapeutics
Proteins

Keywords

  • AKT2
  • BCAM
  • Cancer-specific fusion gene
  • Fusion kinase
  • High-grade serous ovarian cancer

ASJC Scopus subject areas

  • General

Cite this

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma. / Kannan, Kalpana; Coarfa, Cristian; Chao, Pei Wen; Luo, Liming; Wang, Yan; Brinegar, Amy E.; Hawkins, Shannon; Milosavljevic, Aleksandar; Matzuk, Martin M.; Yen, Laising.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 11, 17.03.2015, p. E1272-E1277.

Research output: Contribution to journalArticle

Kannan, Kalpana ; Coarfa, Cristian ; Chao, Pei Wen ; Luo, Liming ; Wang, Yan ; Brinegar, Amy E. ; Hawkins, Shannon ; Milosavljevic, Aleksandar ; Matzuk, Martin M. ; Yen, Laising. / Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 11. pp. E1272-E1277.
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AU - Luo, Liming

AU - Wang, Yan

AU - Brinegar, Amy E.

AU - Hawkins, Shannon

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AB - 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.

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