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Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Identification of hyper-rewired genomic stress non-oncogene addiction genes across 15 cancer types
Jessica Xin Hjaltelin1, Jose M G Izarzugaza2, Lars Juhl Jensen1
11Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Abstract:
Non-oncogene addiction (NOA) genes are essential for supporting the stress-burdened phenotype of tumours and thus vital for their survival. Although NOA genes are acknowledged to be potential drug targets, there has been no large-scale attempt to identify and characterise them as a group across cancer types. Here we provide the first method for the identification of conditional NOA genes and their rewired neighbours using a systems approach. Using copy number data and expression profiles from The Cancer Genome Atlas (TCGA) we performed comparative analyses between high and low genomic stress tumours for 15 cancer types. We identified 101 condition-specific differential coexpression modules, mapped to a high-confidence human interactome, comprising 133 candidate NOA rewiring hub genes. We observe that most modules lose coexpression in the high-stress state and that activated stress modules and hubs take part in homoeostasis maintenance processes such as chromosome segregation, oxireductase activity, mitotic checkpoint (PLK1 signalling), DNA replication initiation and synaptic signalling. We furthermore show that candidate NOA rewiring hubs are unique for each cancer type, but that their respective rewired neighbour genes largely are shared across cancer types.
Insights
This study introduces a novel method to identify non-oncogene addiction (NOA) genes and their network neighbors in tumors. It reveals cancer-specific NOA hubs and shared neighbor genes crucial for tumor survival under stress.
Area of Science:
- Genomics
- Systems Biology
- Cancer Research
Background:
- Non-oncogene addiction (NOA) genes are crucial for tumor survival under stress.
- Identifying and characterizing NOA genes across cancer types is vital for drug development but has not been done at scale.
Purpose of the Study:
- To develop a systems-based method for identifying conditional NOA genes and their rewired neighbors.
- To characterize these genes and their network interactions across various cancer types.
Main Methods:
- Comparative analysis of genomic stress and expression profiles from The Cancer Genome Atlas (TCGA) across 15 cancer types.
- Identification of condition-specific differential coexpression modules and candidate NOA rewiring hub genes using a high-confidence human interactome.
Main Results:
- 101 condition-specific differential coexpression modules and 133 candidate NOA rewiring hub genes were identified.
- Most modules lost coexpression in high-stress states; activated hubs are involved in homeostasis (e.g., chromosome segregation, DNA replication).
- Candidate NOA rewiring hubs are cancer-type specific, while their neighbor genes are largely shared.
Conclusions:
- The study presents the first large-scale identification of conditional NOA genes and their rewiring networks.
- Findings highlight the unique and shared genetic vulnerabilities across cancer types, offering potential therapeutic targets.
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