Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Nat Commun. 2018 Apr 10;9(1):1357. doi: 10.1038/s41467-018-03867-9.
Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.
磷酸肌醇 3-激酶（PI3K）通路的失调导致肿瘤的发生和发展。在这里，我们确定在中国乳腺癌患者中 PIK3CA（44%）、PIK3R1（17%）、AKT3（15%）和 PTEN（12%）的体细胞突变是普遍存在且多样化的，其中鉴定出 60 种新突变。很大比例的肿瘤存在多种突变，尤其是 PIK3CA 加 PIK3R1 突变（9.0%）。接下来，我们开发了一种基于重组的突变条形码（ReMB）文库，用于鉴定在增殖和药物反应中具有克隆优势的影响性突变。排名最高的 PIK3CA 和 PIK3R1 突变包括先前报道的有害突变，以及具有未知意义的突变。这些 PIK3CA 和 PIK3R1 影响性突变表现出相互排斥的模式，导致致癌和 PI3K 通路的过度活跃。PIK3CA 影响性突变与激素受体阳性密切相关。总的来说，这些发现推进了我们对乳腺癌中 PI3K 影响性突变的理解，对精准肿瘤学中 PI3K 靶向治疗具有重要意义。
