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Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.

ABSTRACT: Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBP? and C/EBP?. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in > 50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer's disease.

SUBMITTER: Chen JC

PROVIDER: S-EPMC4194029 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.

Chen James C JC Alvarez Mariano J MJ Talos Flaminia F Dhruv Harshil H Rieckhof Gabrielle E GE Iyer Archana A Diefes Kristin L KL Aldape Kenneth K Berens Michael M Shen Michael M MM Shen Michael M MM Califano Andrea A

Cell 20141001 2

Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our anal ...[more]

PMID: 25303533

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Dataset Information

Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.

Publications

Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.

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