Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma
Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma
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DOI：
10.1073/pnas.1501735112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Yen, Laising
中科院分区：
文献类型：
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作者：
Kannan, Kalpana;Coarfa, Cristian;Yen, Laising
高级别浆液性卵巢癌（HGSC）是女性中最致命的癌症之一。过度的基因组重排，预计会产生融合癌基因，是这种癌症的标志。在这里，我们报告了BCAM（一种膜粘附分子）和AKT 2（PI 3 K信号通路中的一种关键激酶）之间的癌症特异性基因融合。这种融合存在于7%的60名患者的癌症测试，考虑到这种恶性肿瘤的高度异质性的显着频率。此外，我们提供了BCAM-AKT 2在患者肿瘤中被翻译成框内融合蛋白的直接证据。所得的AKT 2融合激酶是膜相关的，组成性磷酸化的，并作为细胞中的功能性激酶被激活。与内源性AKT 2不同，其活性受到外部刺激的严格调节，BCAM-AKT 2逃脱了外部刺激的调节。此外，使用CRISPR/Cas9系统通过染色体易位产生的BCAM-AKT 2融合基因导致OVCAR 8和HEK-293 T细胞系中的病灶形成，表明BCAM-AKT 2是致癌的。总之，结果表明BCAM-AKT 2表达是HGSC中AKT 2激酶活化的新机制。BCAM-AKT 2是HGSC中唯一被证明翻译具有致癌特性的异常但功能性激酶融合蛋白的融合基因。这种复发性基因组改变是HGSC定制治疗的临床相关亚型的潜在治疗靶点和标志物。
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.