title: Network Analysis Reveals A Signaling Regulatory Loop in the PIK3CA-mutated Breast Cancer Predicting Survival Outcome.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shauna R
authors.initials: SR
authors.lastname: McGee
authors.affiliation: National Research Council Canada, Montreal, QC H4P 2R2, Canada.
authors.forename: Chabane
authors.initials: C
authors.lastname: Tibiche
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Trifiro
authors.affiliation: National Research Council Canada, Montreal, QC H4P 2R2, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 2B2, Canada; Center for Bioinformatics, McGill University, Montreal, QC H3G 0B1, Canada; Center for Health Genomics and Informatics, Calgary, AB T2N 4N1, Canada; Department of Biochemistry & Molecular Biology/Medical Genetics/Oncology, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Calgary, AB T2N 4N1, Canada; Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N1, Canada; O'Brien Institute for Public Health, Calgary, AB T2N 4N1, Canada. Electronic address: edwin.wang@ucalgary.ca.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Breast cancer; Genome sequencing; Network analysis; Network motif; PIK3CA mutation; Survival