Abstract 3750: Functional analysis of the Fanconi Anemia pathway in primary lung tumors

Abstract

Abstract The Fanconi Anemia (FA) pathway is a major mechanism of homologous recombination DNA repair in response to genotoxic insults. Lack of formation of FANCD2 foci has been reported as a predictor of cisplatin and mitomycin C (MMC) sensitivity in cancer cells. Given that this pathway plays essential roles in response to the DNA damage, cancers with defective FA pathway are expected to be more sensitive to DNA cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have developed a test to identify tumors with defective FA pathway using paraffin embedded tissues. Paraffin embedded lung primary cancer specimens were subjected to immunofluorescence microscopy (IF) analysis to evaluate the status of FancD2 subnuclear foci formation, Ki67 protein expression and DAPI staining of nuclei simultaneously in order to eliminate false negative tumor specimens due to absence of tumor cells or low proliferation. Additional validation using FA defective PD220 and PD20 cell-lines as well as fresh tumor tissues was done; IF analysis and Western blotting analysis of FDACD2 protein mono-ubiqutination were performed. The ratio of FANCD2 foci negative tumor was 20% among 20 paraffin embedded non-small cell lung cancer samples analyzed. Histological characteristics of the defective tumors include large cell carcinoma and adenocarcinoma. The proposed immunofluorecence staining method evaluates functional status of FA pathway using paraffin embedded tissues even after long term storage. Given the clinical availability of agents targeting alternative mechanisms of repair, the status of FA pathway may be an important biomarker for personalized therapeutic treatment in patients with lung cancers. A clinical trial to validate this hypothesis is under way. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3750.