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. PIK3...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. PIK3 CA 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 PIK3 CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3 CA mutations. To understand the function of PIK3 CA mutations in luminal A breast cancer, we applied our recentlyproposed 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 PIK3 CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3 CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3 CA 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 PIK3 CAmutated luminal A patients.展开更多
基金supported by the National Research Council Canada (NRC) Cancer Genomics Program, Prostate Cancer Canada Movember Discovery Grant (Grant No. D2013-34)the Alberta Innovates Health Solution Translational Health Chairs Program+1 种基金fellowship awards from the Canadian Institute of Health Research (CIHRthe Fonds de Recherche Sante′Quebec (FRQS)
文摘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. PIK3 CA 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 PIK3 CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3 CA mutations. To understand the function of PIK3 CA mutations in luminal A breast cancer, we applied our recentlyproposed 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 PIK3 CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3 CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3 CA 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 PIK3 CAmutated luminal A patients.
