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.

中文翻译：

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在三阴性乳腺癌和浆液性卵巢癌中，BLM的过度表达会促进DNA损伤并增加对铂盐的敏感性。

背景基于铂的疗法是针对三阴性乳腺癌和卵巢癌患者的子集的有效疗法。为了增加反应速率并减少不必要的使用，需要预测治疗反应的健壮生物标志物。患者和方法我们在两个独立的新辅助顺铂治疗的队列研究中，对敏感性与耐药性三阴性乳腺癌相比，进行了基因表达和DNA拷贝数差异分析的综合基因组方法。通过过表达，敲低和靶向抑制剂治疗，在体外研究了重要命中的功能相关性。结果我们确定了两个基因，Bloom解旋酶（BLM）和Fanconi贫血补充组I（FANCI），在铂敏感病例中，它们的DNA拷贝数和基因表达均增加。卵巢癌中这两个基因表达的增加也与铂有关，但与紫杉烷反应无关。作为功​​能验证，我们发现BLM的过表达促进DNA损伤并诱导对顺铂的敏感性，但对紫杉醇的敏感性没有影响。结论基于BLM和FANCI基因表达水平的生物标志物可能是三阴性乳腺癌和卵巢癌中铂敏感性的潜在预测指标。