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Network Analysis Reveals A Signaling RegulatoryLoop in PIK3CA-mutated Breast Cancer Predicting Survival Outcome

Network Analysis Reveals A Signaling Regulatory Loop in PIK3CA-mutated Breast Cancer Predicting Survival Outcome
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摘要 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. 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.
出处 《Genomics, Proteomics & Bioinformatics》 SCIE CAS CSCD 2017年第2期121-129,共9页 基因组蛋白质组与生物信息学报(英文版)
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 fellowship awards from the Canadian Institute of Health Research (CIHR the Fonds de Recherche Sante′Quebec (FRQS)
关键词 Network analysis PIK3CA mutation Network motif Breast cancer Genome sequencing SURVIVAL Network analysis PIK3CA mutation Network motif Breast cancer Genome sequencing Survival
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