Identification of Networks of Co-Occurring, Tumor-Related DNA Copy Number Changes Using a Genome-Wide Scoring Approach

Identification of Networks of Co-Occurring, Tumor-Related DNA Copy Number Changes Using a Genome-Wide Scoring Approach

Klijn, C.
Bot, J.
Adams, D.J.
Reinders, M.
Wessels, L.
Jonkers, J.

Electrical Engineering, Mathematics and Computer Science

Mediamatics

2010-01-01

Tumorigenesis is a multi-step process in which normal cells transform into malignant tumors following the accumulation of genetic mutations that enable them to evade the growth control checkpoints that would normally suppress their growth or result in apoptosis. It is therefore important to identify those combinations of mutations that collaborate in cancer development and progression. DNA copy number alterations (CNAs) are one of the ways in which cancer genes are deregulated in tumor cells. We hypothesized that synergistic interactions between cancer genes might be identified by looking for regions of co-occurring gain and/or loss. To this end we developed a scoring framework to separate truly cooccurring aberrations from passenger mutations and dominant single signals present in the data. The resulting regions of high co-occurrence can be investigated for between-region functional interactions. Analysis of high-resolution DNA copy number data from a panel of 95 hematological tumor cell lines correctly identified co-occurring recombinations at the T-cell receptor and immunoglobulin loci in T- and B-cell malignancies, respectively, showing that we can recover truly cooccurring genomic alterations. In addition, our analysis revealed networks of co-occurring genomic losses and gains that are enriched for cancer genes. These networks are also highly enriched for functional relationships between genes. We further examine sub-networks of these networks, core networks, which contain many known cancer genes. The core network for co-occurring DNA losses we find seems to be independent of the canonical cancer genes within the network. Our findings suggest that large-scale, low-intensity copy number alterations may be an important feature of cancer development or maintenance by affecting gene dosage of a large interconnected network of functionally related genes.

http://resolver.tudelft.nl/uuid:8135ff97-2d21-4645-a60b-1480c8ee6d61

https://doi.org/10.1371/journal.pcbi.1000631

Public Library of Science

1553-734X

Plos Computational Biology, 6 (1), 2010

Institutional Repository

journal article

(c) 2010 Klijn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.