High-Resolution Genomic Profiling of Carboplatin Resistance in Early-Stage Epithelial Ovarian Carcinoma

Abstract

Chemotherapy resistance remains a major obstacle to successful treatment of ovarian cancer patients. Therefore, increased knowledge of underlying mechanisms and identification of predictive factors are of great importance. Standard treatment for ovarian carcinoma is surgery followed by platinum-based chemotherapy. In this study, we aimed to search for genes or genomic regions involved in platinum resistance in ovarian carcinoma. Array-based comparative genomic hybridization (CGH) was used to identify genetic alterations in 32 early-stage epithelial ovarian carcinomas homogeneously treated with single-agent carboplatin. The arrays contain 33,370 bacterial artificial chromosome (BAC) clones and form a contiguous and tiling coverage of the human genome with an average resolution of ∼100 kb. We found certain genetic changes associated with carboplatin response. Gains in 1q25.1–q41 were significantly more frequent in carboplatin-resistant tumours. In this region, we further detected two smallest regions of overlap (SRO) at 1q25.2 and 1q32.2 (∼690 and ∼830 kb in size, respectively). Interestingly, we found some regions that were lost exclusively in the sensitive tumours 17q24.1, Xq21.33–q22.1, and 6 regions in 15q. We also detected genetic differences with regard to histologic subtype. Gain in 8q was found highly associated with serous and clear cell subtypes, and an SRO was identified at 8q24.22–q24.23. The genomic regions found altered in this study confirm some of our previous metaphase CGH results. The alteration found in chromosome arm 1q was verified and specified, and is therefore of great interest as a candidate for predictive markers. Identifying predictive markers of chemosensitive and chemoresistant disease would greatly help in the choice of chemotherapy in the clinic, and thus improve treatment of women with ovarian cancer.