Abstract 1783: Examination of the chemoresistant subpopulation in ovarian cancer identifies DNA repair genes contributing to survival after primary therapy.
Authors: Erickson Britt K. , Steg Adam D. , Dobbin Zach C. , Katre Ashwini A. , Alvarez Ronald D. , Landen Charles N. 
Published: August 2014

Background: Although the majority of patients with advance stage epithelial ovarian cancer respond to platinum and taxane-based chemotherapy, most patients ultimately develop recurrent disease, demonstrating that a select subpopulation of cancer cells is capable of surviving this initial challenge. Tumor heterogeneity makes identification of genes most relevant to this process difficult. A comparison of matched primary tumors and tumors still present after initial chemotherapy could shed light onto which genes are contributing to survival after primary therapy. DNA repair pathways may be important in this process.

Methods: After IRB approval, 45 patients were identified in whom both primary and secondary (recurrent) tumor samples were collected. For 12 of these, the recurrent tumor was collected immediately at the completion of primary therapy, therefore representing the population that survived chemotherapy and referred to as “persistent disease”. Tumor cells were extracted from FFPE slides by laser capture microdissection and subjected to a qPCR array consisting of 84 genes participating in DNA damage response and repair (SA Biosystems, Qiagen).

Gene expression was compared between the two samples, and select genes identified as significantly different were validated with qPCR. Expression of genes of interest was also examined in 3 pairs of matched chemosensitive/chemoresistant ovarian cancer cell lines: A2780/A2780cp55, HeyA8/HeyA8MDR, and SKOV3ip1/SKOV3TRip2 both at baseline, and with 24-hour exposure to carboplatin.

Levels of gene expression were compared with the Wilcoxon signed-rank sum test for non-parametric data, and the student's t-test for normally distributed data.

Results: Of 84 genes evaluated in the DNA repair pathway array, 7 were significantly different (p&lt;0.05) between the primary and persistent patient tumors: SUMO1, CDKN1A (p21), Microcephalin 1, DDB2, HUS1, RAD9A, and APEX1. Additionally, trends towards significance (p&lt;0.10) were noted by overexpression in DDB1, RAD18, XRCC3, PARP1, and BARD1; and reduced expression of MSH2 and ATRX. Trends seen in BARD-1, APEX1 and ATRX were mirrored in the highly cisplatin-resistant cell lines. Decreased expression of MSH2 was mirrored in the taxane-resistant lines compared to the parental lines, suggesting a role for MSH2 in taxane resistance. Short-term treatment of parental A2780ip1 confirmed that BARD1 is induced by exposure to carboplatin.

Conclusions: We have identified several genes participating in DNA repair pathways that may contribute to survival of primary therapy in epithelial ovarian cancer. Such genes might be targeted for downregulation in an attempt to overcome the ability of cancer cells to repair DNA damage induced by chemotherapy and reduce rates of relapsed disease.

Citation Format: Britt K. Erickson, Adam D. Steg, Zach C. Dobbin, Ashwini A. Katre, Ronald D. Alvarez, Charles N. Landen. Examination of the chemoresistant subpopulation in ovarian cancer identifies DNA repair genes contributing to survival after primary therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1783. doi:10.1158/1538-7445.AM2013-1783