Network Analysis Reveals A Signaling Regulatory Loop in the PIK3CA-mutated Breast Cancer Predicting Survival Outcome.
Network Analysis Reveals A Signaling Regulatory Loop in the PIK3CA-mutated Breast Cancer Predicting Survival Outcome.
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DOI：
10.1016/j.gpb.2017.02.002
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Wang E
中科院分区：
文献类型：
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作者：
McGee SR;Tibiche C;Trifiro M;Wang E
即使在相同病理类型的癌症患者中，突变基因也很少常见，因此，解释基因组测序数据非常具有挑战性，并且难以预测临床结果。PIK3CA是少数几个在肿瘤中相对常见的突变基因之一。例如，超过46.6%的luminal-A乳腺癌样本存在PIK3CA突变，而所有乳腺癌样本中PIK3CA突变的比例仅为35.5%。为了了解PIK3CA突变在管腔A乳腺癌中的功能，我们应用我们最近提出的癌症标志网络框架来研究PIK3CA突变的管腔A肿瘤中的网络基元。我们发现超过70%的pik3ca突变的腔内A肿瘤包含一个正调节环，其中主调节因子（PDGF-D），第二调节因子（FLT1）和输出节点（SHC1）共同作用。重要的是，我们发现在肿瘤中携带PIK3CA突变和这种正调节环的腔内A乳腺癌患者的生存期明显长于仅在肿瘤中携带PIK3CA突变的患者。这些发现表明，PIK3CA突变在管腔A患者中的潜在分子机制可能参与一个正调节环，并且正调节环（PDGF-D/FLT1/SHC1）对PIK3CA突变的管腔A患者的生存具有预测能力。
Mutated genes are rarely common even in the same pathological type between cancer patients and as such, it has been very challenging to interpret genome sequencing data and difficult to predict clinical outcomes. PIK3CA is one of a few genes whose mutations are relatively popular in tumors. For example, more than 46.6% of luminal-A breast cancer samples have PIK3CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3CA mutations. To understand the function of PIK3CA mutations in luminal A breast cancer, we applied our recently-proposed Cancer Hallmark Network Framework to investigate the network motifs in the PIK3CA-mutated luminal A tumors. We found that more than 70% of the PIK3CA-mutated luminal A tumors contain a positive regulatory loop where a master regulator (PDGF-D), a second regulator (FLT1) and an output node (SHC1) work together. Importantly, we found the luminal A breast cancer patients harboring the PIK3CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3CA mutations in luminal A patients can participate in a positive regulatory loop, and furthermore the positive regulatory loop (PDGF-D/FLT1/SHC1) has a predictive power for the survival of the PIK3CA-mutated luminal A patients.