Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer.

Agnieszka Dansonka-Mieszkowska,Bozena Konopka,Magdalena Kulesza,Anna Balcerak,Joanna Moes-Sosnowska,Lukasz M Szafron,Jolanta Kupryjanczyk,Jan K Siwicki,Renata Zub,Urszula Piekarska,Barbara Pienkowska-Grela,Iwona K Rzepecka,Joanna Parada,Mariusz Kulinczak,Radoslaw Madry,Martyna Lukasik,Agnieszka Budzilowska

doi:10.18632/oncotarget.24878

Agnieszka Dansonka-Mieszkowska, Bozena Konopka + Show 15 more

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https://doi.org/10.18632/oncotarget.24878

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Abstract

EMSY, a BRCA2–associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.

Highlights

Ovarian cancer is the most lethal malignancy of a female reproductive system
The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in ovarian cancer (OvCa) patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well
Our results revealed that changes in EMSY expression may influence cancer prognosis and significantly affect tumor response to chemotherapy

Summary

Introduction

Ovarian cancer is the most lethal malignancy of a female reproductive system. Due to the lack of specific symptoms and markers, most women are diagnosed in advanced stages of the disease. Improvements in ovarian cancer treatment could be achieved by better understanding the molecular pathogenesis of this malignancy. This may help identify molecular factors that determine success of the applied therapy and potentially allow for developing new methods of ovarian cancer treatment. Platinum- and taxane-based regimens are routinely used as a first-line, postsurgical therapy in patients with FIGO stage II to IV disease. Taxanes bind to ß-tubulin and stabilize microtubules by promoting their assembly and inhibiting disassembly [3]. This leads to a cell cycle arrest in the G2/M phase, cell division inhibition and apoptosis

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