|Title:||Toward bridging the gap between genotype and phenotype - systems biology approach|
Teresa M. Przytycka
NCBI / NIH, Washington DC, USA
In complex diseases various combinations of genomic perturbations lead to the same phenotype suggesting that on the molecular level, combinations of genomic perturbations might dys-regulate the same cellular pathways. Such pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases and the identification of potential drug targets. In order to provide an integrated perspective on complex disease mechanisms, we developed a novel computational method to simultaneously identify causal genes anddys-regulated pathways. Applying our method to sets of genomic alterations and gene expression profiles of 158 Glioblastoma multiforme (GBM) patients we uncovered candidate causal genes and causal paths that are potentially responsible for the altered expression of disease genes. Our results indicate that different genomic perturbations indeed dys-regulate the same functional pathways, supporting a pathway-centric perspective of cancer. While copy number alterations and gene expression data of glioblastoma patients provided opportunities to test our approach, our method can be applied to any disease system where genetic variations play a fundamental causal role.