Abstract
Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript SPON1-TRIM29 in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing SPON1-TRIM29 exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of SPON1-TRIM29 fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that SPON1-TRIM29-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the SPON1-TRIM29 fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript.
Highlights
Ovarian cancer is a common gynecological malignancy among females, which accounts for an estimated 313,959 new cases and 207,252 deaths worldwide per year [1]
Poly (ADP-ribose) polymerase (PARP) inhibitor is a new option for maintenance therapy in patients with ovarian cancer who respond to platinum-based chemotherapy, those who have tumors with the BRCA mutation or homologous recombination deficiency [4]
Our findings suggest that the SPON1-TRIM29 fusion gene could contribute to tumor aggressiveness in a population of ovarian cancer and that the new biomarker may be applied as a therapeutic target for fusion-positive tumors
Summary
Ovarian cancer is a common gynecological malignancy among females, which accounts for an estimated 313,959 new cases and 207,252 deaths worldwide per year [1]. The recent application of molecular targeted drugs in ovarian cancer treatment has improved patient prognosis Among these drugs, poly (ADP-ribose) polymerase (PARP) inhibitor is a new option for maintenance therapy in patients with ovarian cancer who respond to platinum-based chemotherapy, those who have tumors with the BRCA mutation or homologous recombination deficiency [4]. We recently showed transcriptomic profiles of clinical ovarian cancers based on RNA-seq analysis and identified CPNE8 and BHLHE41 as prototypic upregulated genes, predominantly in CCC and HGSC, respectively [6]. We identified new and known mutations of tumor-associated genes, such as TP53, in ovarian cancer specimens based on RNA-seq [7]. We performed RNA-seq analysis of 32 ovarian cancer tissues and 6 normal ovary tissues, and identified a novel fusion transcript SPON1-TRIM29 from a recurrent HGSC tumor. Our findings suggest that the SPON1-TRIM29 fusion gene could contribute to tumor aggressiveness in a population of ovarian cancer and that the new biomarker may be applied as a therapeutic target for fusion-positive tumors
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