Abstract 969: Amplifications, gene fusions, and therapeutic targets in triple negative and refractory ER+ and HER2+ breast cancers
| Autor: | Tara Holley, Zhongwu Lai, Kevin Webster, Wibhav Tembe, Michael T. Barrett, Deborah Morosini, Lihua Yu, Elizabeth Lenkiewicz, Lisa Evers, Haiguo Wu |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Cancer Research. 72:969-969 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2012-969 |
| Popis: | Breast cancer is known to be heterogeneous and choices of targeted therapy are still limited for refractory estrogen receptor positive (ER+), refractory HER2+, and triple negative (TNBC) breast cancer. In order to identify novel drug targets that are either focally amplified or involved in fusion or translocation events in such disease segments, we applied high resolution DNA copy number profiling and whole genome sequencing to a set of DNA content sorted breast cancer samples. We first applied DNA-content based flow cytometry to purify diploid and aneuploid cells in each of 54 samples. Purified populations of both aneuploid and diploid cells were then subjected to high resolution aCGH profiling. Our initial analysis of high resolution copy number profiling data identified a list of genes focally amplified and harboring break points. We then selected 8 of these samples (four ER+ and four triple negative) for whole genome sequencing to identify their fusion partners. Paired-end sequencing data from HiSeq for each flow sorted sample was aligned against the human genome. A custom analysis workflow based on published software tools and custom developed scripts for computationally predicting structural variation events was implemented. Paired ends that mapped to discontinuous regions in the genome were merged with our aCGH data to identify candidate gene fusions, inversions, and translocations in each sample. Automatic scan and custom examination for pair-ends mapped to discontinuous genomic regions identified a list of novel gene fusion and translocation candidates. A subset of such fusion candidates showed precise break point position concordance across the NGS and aCGH data and equal copy number amplification of two fusion partners, further strengthening our confidence that such genes are indeed involved in fusion and translocation events. These candidates include transcription factors (e.g. ZNF492), kinases (e.g. DYRK1A), and phosphatases (e.g. PTPRG). Some of these fusion genes are known to be involved in fusion in other diseases or tumor types but have not been reported in breast cancer, such as AUTS2, which is reported as translocation partner in autism and mental retardation patients and B-cell ALL, and MECOM (aka EVI1/MDS1), which is fused with AML1 in AML patients. Others are completely novel such as BICD1-ZNF492. In conclusion, we have successfully identified a list of fusions genes in ER+ refractory and triple negative breast cancer patients by combining high resolution aCGH profiling of DNA copy number analysis and whole genome sequencing. The next step is to validate the expression of these fusion proteins and their functional relevance to breast cancer. The driver fusion genes identified can provide potential therapeutic targets for ER+ refractory and TN breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 969. doi:1538-7445.AM2012-969 |
| Databáze: | OpenAIRE |
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