title: A computational model to predict bone metastasis in breast cancer by integrating the dysregulated pathways.
abstract: BACKGROUND
  Although there are a lot of researches focusing on cancer prognosis or prediction of cancer metastases, it is still a big challenge to predict the risks of cancer metastasizing to a specific organ such as bone. In fact, little work has been published for such a purpose nowadays.
  
  
  METHODS
  In this work, we propose a Dysregulated Pathway Based prediction Model (DPBM) built on a merged data set with 855 samples. First, we use bootstrapping strategy to select bone metastasis related genes. Based on the selected genes, we then detect out the dysregulated pathways involved in the process of bone metastasis via enrichment analysis. And then we use the discriminative genes in each dysregulated pathway, called as dysregulated genes, to construct a sub-model to forecast the risk of bone metastasis. Finally we combine all sub-models as an ensemble model (DPBM) to predict the risk of bone metastasis.
  
  
  RESULTS
  We have validated DPBM on the training, test and independent sets separately, and the results show that DPBM can significantly distinguish the bone metastases risks of patients (with p-values of 3.82E-10, 0.00007 and 0.0003 on three sets respectively). Moreover, the dysregulated genes are generally with higher topological coefficients (degree and betweenness centrality) in the PPI network, which means that they may play critical roles in the biological functions. Further functional analysis of these genes demonstrates that the immune system seems to play an important role in bone-specific metastasis of breast cancer.
  
  
  CONCLUSIONS
  Each of the dysregulated pathways that are enriched with bone metastasis related genes may uncover one critical aspect of influencing the bone metastasis of breast cancer, thus the ensemble strategy can help to describe the comprehensive view of bone metastasis mechanism. Therefore, the constructed DPBM is robust and able to significantly distinguish the bone metastases risks of patients in both test set and independent set. Moreover, the dysregulated genes in the dysregulated pathways tend to play critical roles in the biological process of bone metastasis of breast cancer.
authors.forename: Xionghui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Computer, Wuhan University, Wuhan, P,R, China. liujuan@whu.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D018570:Risk Assessment