Abstract 2751: Fanconi anemia pathway and DNA repair-based prognostic signatures in ovarian cancer

Abstract

Abstract Introduction: Of the 21,000 patients diagnosed annually in the United States with epithelial ovarian cancer, approximately 75% present with Stage III-IV disease. The vast majority of these patients are treated with cytotoxic chemotherapy regimens, where clinical response may be associated with activity of DNA repair pathways in tumors. Characterizing these repair pathways should help predict clinical response to specific chemotherapeutic agents. Methods: We devised a set of 150 DNA repair genes with documented functional importance in key DNA repair pathways including base excision repair (BER), Fanconi Anemia (FA), homologous recombination (HR), mismatch repair (MMR), non-homologous end joining (NHEJ), nucleotide excision repair (NER) and translesion synthesis (TLS). We extracted microarray expression data for these genes for 511 tumors and 8 normal specimens using data from Agilent Custom 244K Gene Expression and Affymetrix Human Genome U133A arrays. We performed Significance Analysis of Microarrays (SAM) to determine which of the 150 DNA repair genes were significantly more expressed in tumor vs. normal specimens. We then generated Kaplan-Meier survival curves using overall survival data. Results: Using the Affymetrix data, we identified 57 genes that were significantly up-regulated with a median fold change of 3.15 (range, 2.03-6.07) and 6 genes that were significantly down-regulated with a median fold change of 2.67 (range, 2.11-4.74) among tumor vs. normal tissue samples by SAM (delta 1.013, false discovery rate 0%). SAM using the Agilent data showed similar results; a total of 46 genes were significant hits in both datasets. A DNA repair signature consisting of genes significant in both platforms was defined and revealed a correlation between high expression values and decreased survival (median overall survival 4.5 vs. 5.2 years, log-rank p = 0.0086). DNA repair signatures specific to individual repair pathways were defined and demonstrated that high FA pathway (BRCA2, FAAP24, FANCA, FANCE, FANCG, FANCI and PALB2) expression in particular was inversely correlated with survival (median overall survival 4.1 vs. 5.2 years, log-rank p = 0.029 and 0.019 for the Affymetrix and Agilent datasets, respectively). Conclusion: Evidence from literature supports the critical role of the Fanconi Anemia (FA) pathway in repairing DNA damage caused by platinum-based agents such as cisplatin and carboplatin, commonly utilized to treat ovarian cancer patients. We show that a DNA repair signature specific to FA can be utilized to identify patients with high FA expression, whom we hypothesize may be more resistant to traditional platinum-based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2751. doi:10.1158/1538-7445.AM2011-2751