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.

Overexpression of IL-7 enhances cisplatin resistance in glioma

“…Prasad et al 11 analyzed the genomic aberrations and genes in cisplatin-resistant ovarian cancer cells using high definition cytogenetics and oligonucleotide aCGH. Osterberg et al 12 explored high-resolution genomic profiling of carboplatin resistance in early-stage epithelial ovarian carcinoma. Hattinger et al 13 detected the genomic imbalances associated with methotrexate resistance in human osteosarcoma cell lines by comparative genomic hybridization-based techniques.…”

Potential predictive markers of chemotherapy resistance in stage III ovarian serous carcinomas

“…To our knowledge, there are only a few reports on chemotherapy resistance in ovarian cancer using array CGH [12-15]. There are also prior studies using conventional metaphase CGH to investigate platinum resistance in ovarian cancer [16-19].…”

“…A useful key technique to study CNAs with is the array format of comparative genomic hybridization (CGH), a high-resolution genome-wide screening method that detects and maps copy number changes in the tumor genome. There are a few reports utilizing array CGH when studying chemotherapy resistance in ovarian cancer [12-15], and in addition there are a number of reports performed with conventional metaphase CGH [16-19]. Unfortunately, the overall concurrence is low, pin-pointing the need of further studies.…”

Effects of Lewis Y antigen on the gene expression of multiple drug resistance-associated proteins in human ovarian cancer RMG-I-H cells

“…Because of drug resistance of ovarian cancer cells, approximately 70% of ovarian cancer patients relapse within 2 years after surgery [2]. Therefore, clarification of the molecular mechanism behind drug resistance in ovarian cancer is of great significance in improving clinical efficacy and patient survival.…”