title: A sparse regulatory network of copy-number driven gene expression reveals putative breast cancer oncogenes.
abstract: Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the-art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis- versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation.
  
  
  BACKGROUND
  An R package named lol is available from www.markowetzlab.org/software/lol.html.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom. yy341@cam.ac.uk
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Yuan
authors.forename: Christina
authors.initials: C
authors.lastname: Curtis
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D016014:Linear Models; D009857:Oncogenes