Abstract
Abstract Background: The mechanisms underlying resistance to chemotherapy in ovarian cancer are incompletely understood. Identifying genetic alterations associated with treatment response is decisive in the determination of which patients may benefit from adjuvant chemotherapy. Methods: Biopsies were collected from twenty patients diagnosed with ovarian cancer who were subjected to post-operative taxane- and platinum-containing chemotherapy. Patients were selected for genetic analyses based on response to chemotherapy, determined as time to relapse (10 sensitive and 10 resistant patients). A panel of 620 genes, including known cancer driver genes, as well as genes involved in DNA repair were analysed by massively parallel sequencing. Alignment and mutation calling was performed using MiSeq Reporter, with further manual filtering of variants to exclude common SNPs. Validation of low quality mutation calls was done by Sanger sequencing. Results: A median of 6 genes (range: 3 - 45) per patient was found to harbour non-synonymous mutations. Among previously identified driver genes in ovarian cancer, we found mutations in TP53, BRCA1, CDK12, NF1 and CSMD3. These mutations were more common among patients with more advanced disease and higher grade. For example, TP53 mutations were found in 10 out of 12 patients with high grade, stage 3c or 4 disease, and in 2 out of 5 with lower stage and/or grade. One patient was found to have a tumor potentially of a hyper-mutator phenotype with 49 mutations in 45 genes identified within our gene panel. With respect to treatment efficacy, 73 and 40 genes were found to be mutated exclusively in patients with a good and poor response to treatment, respectively. Conclusion: We describe the profile of mutations in cancer driver genes and DNA repair genes among patients suffering from ovarian cancer according to treatment response. Citation Format: Einar Birkeland, Rakel Blaalid, Merete Bjørnslett, Anne Dørum, Per Eystein Lønning, Stian Knappskog. Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2014-2833
Published Version
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