title: Deciphering causal and statistical relations of molecular aberrations and gene expressions in NCI-60 cell lines.
abstract: BACKGROUND
  Cancer cells harbor a large number of molecular alterations such as mutations, amplifications and deletions on DNA sequences and epigenetic changes on DNA methylations. These aberrations may dysregulate gene expressions, which in turn drive the malignancy of tumors. Deciphering the causal and statistical relations of molecular aberrations and gene expressions is critical for understanding the molecular mechanisms of clinical phenotypes.
  
  
  RESULTS
  In this work, we proposed a computational method to reconstruct association modules containing driver aberrations, passenger mRNA or microRNA expressions, and putative regulators that mediate the effects from drivers to passengers. By applying the module-finding algorithm to the integrated datasets of NCI-60 cancer cell lines, we found that gene expressions were driven by diverse molecular aberrations including chromosomal segments' copy number variations, gene mutations and DNA methylations, microRNA expressions, and the expressions of transcription factors. In-silico validation indicated that passenger genes were enriched with the regulator binding motifs, functional categories or pathways where the drivers were involved, and co-citations with the driver/regulator genes. Moreover, 6 of 11 predicted MYB targets were down-regulated in an MYB-siRNA treated leukemia cell line. In addition, microRNA expressions were driven by distinct mechanisms from mRNA expressions.
  
  
  CONCLUSIONS
  The results provide rich mechanistic information regarding molecular aberrations and gene expressions in cancer genomes. This kind of integrative analysis will become an important tool for the diagnosis and treatment of cancer in the era of personalized medicine.
authors: Ontario Institute for Cancer Research, Toronto, Canada.
authors: Shyh-Dar
authors: SD
authors: Li
authors: Tatsuaki
authors: T
authors: Tagami
authors: Ying-Fu
authors: YF
authors: Ho
authors: Chen-Hsiang
authors: CH
authors: Yeang
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*
chemical_list: D035683:MicroRNAs; D012334:RNA, Neoplasm