Characterization of EPHA3 intragenic rearrangements in high-grade serous carcinoma progression and recurrence

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Abstract High grade serous ovarian cancer (HGSC) accounts for 80% of ovarian cancer mortality, and no targeted therapies are available for this disease. Previous studies have searched for mutations and gene fusions that drive HGSC, but the clinically actionable discoveries have been underwhelming. Although mutations and gene fusions have been a significant focus of cancer genetics, other types of understudied genomic aberrations are known to be cancer-driving, such as Intragenic genetic rearrangements (IGRs) that result in exons within genes being duplicated or deleted. Some IGRs have been reported to drive growth in tumors, such as EGFR and ERBB2 exon rearrangements that are known to cause activation of these kinases. Our analysis of TCGA pan-cancer data revealed that HGSC exhibits a higher frequency of unbalanced IGR events than all other cancers. Further analysis revealed a potential intragenic duplication of the ephrin-receptor protein-tyrosine kinase EPHA3 that may be present in up to 8.3% of HGSC tumors. EPHA3 is overexpressed in a number of cancer types, where it has been proposed as a cancer driver. We have verified the presence of this aberrant transcript in two ovarian cancer cell lines, including a HGSC cell line. Specific knockdown of this aberrant transcript in the HGSC cell line potently reduced cell viability, suggesting that the in-frame duplication of EPHA3 may promote cancer cell growth. We hypothesize that EPHA3 exon duplications may play a key role in activating this tyrosine kinase, which may promote HGSC progression and recurrence. This proposal seeks to assess the incidence of EPHA3 exon duplications in HGSC, explore its association with tumor recurrence and chemoresistance, characterize the underlying genomic aberrations and protein products, and examine its function in activating EPHA3 signaling and HGSC progression.