Journal
ANNALS OF ONCOLOGY
Volume 29, Issue 4, Pages 903-909Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdy049
Keywords
platinum-based chemotherapy; gene expression-based predictor of treatment sensitivity; triple-negative breast cancer; ovarian cancer
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Funding
- Breast Cancer Research Foundation
- Basser Foundation
- EU FP7 project PREDICT
- NovoNordisk Foundation [16854]
- Hungarian Academy of Sciences [LP2011-015]
- Villum Kann Rasmussen Foundation
- V-Foundation
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Background: Platinum-based therapy is an effective treatment for a subset of triple-negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared with resistant triple-negative breast cancers in two independent neoadjuvant cisplatin-treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum-sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple-negative breast cancer and ovarian cancer.
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