Abstract
Ovarian cancer is the fifth leading cause of cancer death in women. Almost 70% of ovarian cancer deaths are due to the high-grade serous subtype, which is typically detected only after it has metastasized. Characterization of high-grade serous cancer is further complicated by the significant heterogeneity and genome instability displayed by this cancer. Other than mutations in TP53, which is common to many cancers, highly recurrent recombinant events specific to this cancer have yet to be identified. Using high-throughput transcriptome sequencing of seven patient samples combined with experimental validation at DNA, RNA and protein levels, we identified a cancer-specific and inter-chromosomal fusion gene CDKN2D-WDFY2 that occurs at a frequency of 20% among sixty high-grade serous cancer samples but is absent in non-cancerous ovary and fallopian tube samples. This is the most frequent recombinant event identified so far in high-grade serous cancer implying a major cellular lineage in this highly heterogeneous cancer. In addition, the same fusion transcript was also detected in OV-90, an established high-grade serous type cell line. The genomic breakpoint was identified in intron 1 of CDKN2D and intron 2 of WDFY2 in patient tumor, providing direct evidence that this is a fusion gene. The parental gene, CDKN2D, is a cell-cycle modulator that is also involved in DNA repair, while WDFY2 is known to modulate AKT interactions with its substrates. Transfection of cloned fusion construct led to loss of wildtype CDKN2D and wildtype WDFY2 protein expression, and a gain of a short WDFY2 protein isoform that is presumably under the control of the CDKN2D promoter. The expression of short WDFY2 protein in transfected cells appears to alter the PI3K/AKT pathway that is known to play a role in oncogenesis. CDKN2D-WDFY2 fusion could be an important molecular signature for understanding and classifying sub-lineages among heterogeneous high-grade serous ovarian carcinomas.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy in women
To identify fusion transcripts that are transcribed from fusion genes, we sequenced the transcriptome of seven cancer samples from patients with highgrade serous carcinoma (HG-SC)
Since there is still debate about the cell of origin of HG-SC as histologically similar cancers have been identified on the surface of the ovary and fallopian tube [8,9], we performed transcriptome sequencing using two control pools: one pool of RNA from ovaries of 20 noncancerous donors and another pool of RNA from the fallopian tubes of 6 non-cancerous donors
Summary
Ovarian cancer is the most lethal gynecologic malignancy in women. 225,500 women are diagnosed with ovarian cancer with an estimated 140,200 associated deaths annually [1]. HG-SC differs substantially from other subtypes of ovarian carcinoma in their molecular features. Common cancer genes such as TP53 and BRCA1/2 are mutated in 96% and 22% of HGSC patients, respectively [2]. These mutations could contribute to the extensive genome rearrangements and high levels of heterogeneity observed in HG-SC [2]. The high degree of heterogeneity in HG-SC suggests diverse clonal lineages within the same patient and among different patients. Discovery of specific molecular signatures for major clonal lineages is essential for understanding the underlying pathogenesis of HG-SC and for designing personalized treatment
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