McGee Shauna R, Tibiche Chabane, Trifiro Mark, Wang Edwin
National Research Council Canada, Montreal, QC H4P 2R2, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 2B2, Canada; Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
National Research Council Canada, Montreal, QC H4P 2R2, Canada.
Genomics Proteomics Bioinformatics. 2017 Apr;15(2):121-129. doi: 10.1016/j.gpb.2017.02.002. Epub 2017 Apr 7.
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.
即使在癌症患者的相同病理类型中，突变基因也很少见，因此，解读基因组测序数据极具挑战性，预测临床结果也很困难。PIK3CA是少数在肿瘤中突变相对常见的基因之一。例如，超过46.6%的腔面A型乳腺癌样本存在PIK3CA突变，而在所有乳腺癌样本中，只有35.5%含有PIK3CA突变。为了了解PIK3CA突变在腔面A型乳腺癌中的功能，我们应用了我们最近提出的癌症标志网络框架来研究PIK3CA突变的腔面A型肿瘤中的网络基序。我们发现，超过70%的PIK3CA突变的腔面A型肿瘤包含一个正调控环，其中一个主调控因子（PDGF-D）、一个二级调控因子（FLT1）和一个输出节点（SHC1）共同发挥作用。重要的是，我们发现肿瘤中携带PIK3CA突变和这个正调控环的腔面A型乳腺癌患者的生存期明显长于仅肿瘤中携带PIK3CA突变的患者。这些发现表明，腔面A型患者中PIK3CA突变的潜在分子机制可以参与一个正调控环，此外，正调控环（PDGF-D/FLT1/SHC1）对PIK3CA突变的腔面A型患者的生存具有预测能力。
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