Oncotarget

Research Papers:

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

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

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Oncotarget. 2018; 9:17735-17755. https://doi.org/10.18632/oncotarget.24878

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Abstract

Agnieszka Dansonka-Mieszkowska1,*, Lukasz M. Szafron2,*, Joanna Moes-Sosnowska2, Mariusz Kulinczak2, Anna Balcerak3, Bozena Konopka1, Magdalena Kulesza1, Agnieszka Budzilowska1, Martyna Lukasik1, Urszula Piekarska1, Iwona K. Rzepecka1, Joanna Parada2, Renata Zub3, Barbara Pienkowska-Grela4, Radoslaw Madry5, Jan K. Siwicki2 and Jolanta Kupryjanczyk1

1Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland

2Department of Immunology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland

3Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland

4Cytogenetics Laboratory, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland

5Department of Oncology, Poznan University of Medical Sciences, Poznan, Poland

*These authors have contributed equally to this work

Correspondence to:

Agnieszka Dansonka-Mieszkowska, email: [email protected]

Keywords: ovarian cancer; EMSY; polymorphism; gene expression; chemotherapy

Received: March 31, 2017    Accepted: February 28, 2018    Published: April 03, 2018

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.


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