Abstract 2140: Finding co-occurrence and mutual exclusiveness in DNA copy number data
Authors: Christiaan N. Klijn, Jan Bot, Sjoerd Klarenbeek, Ingrid van der Heijden, David J. Adams, Marcel Reinders, Lodewyk Wessels, Jos Jonkers
Journal: Cancer Research (2010)

Abstract Tumorigenesis is a multi-step process of successive (epi)genetic mutations enabling the transformation of normal cells. There has always been a large interest in finding relationships between mutations that interact to promote cancer development. Copy number alterations (CNAs) are one of the ways in which a tumor cell can affect cancer-related genes. We hypothesized that synergistic or redundant oncogenes can be found by looking for regions of co-occurring or mutually exclusive gain and/or loss in array comparative genomic hybridization (aCGH) datasets. To find interacting CNAs we developed a genome-wide framework to separate truly related aberrations from the noisy passenger and dominant single signals present in the data. We designed a score for both co-occurring and mutually exclusive CNAs. This score was then evaluated for every pair of genomic locations. To reduce noise, we used Gaussian convolution on the 2D score-space. From the peaks in this space, we determine networks of related copy number changes. Since our analysis is done in a 2D genome-by-genome space we applied a distributed computing approach to solve the computational complexity. We applied our approach to two different aCGH datasets. A dataset of 95 cell lines derived from hematological malignancies was examined for copy number co-occurrences and a dataset of 68 mouse mammary tumors was examined for mutual exclusiveness. In the hematological cell-line dataset we are able to identify T- and B-cell specific co-occurring losses, showing that we can recover interacting CNAs that are known to be present in the data. Further analyses revealed large networks of copy number loss and gain. The genomic regions associated with these networks were significantly enriched for cancer-associated genes and functionally related genes, hinting at simultaneous deregulation of genes with similar cellular roles. Our findings suggest that perhaps large scale, low intensity CNAs may be an important feature of cancer. They might affect gene dosages of a large interconnected network of functionally related genes, whose loss or gain is not necessarily driven by a few canonical cancer genes. Analysis of aCGH data of mouse mammary tumors revealed several highly mutually exclusive DNA amplifications. We were able to identify several candidate genes from these amplicons using gene expression data and protein immuno-histochemistry. Our discovery of several mutually exclusive high-level amplicons shows that there might be a redundant role for amplification of these strong proliferation-associated genes. Although many single aberrations in tumors have been studied and investigated, our study describes, to our knowledge, the first high-resolution genome-wide search for interacting aberrations. Our approach offers a methodology to reveal novel, functional networks of copy number changes associated with oncogenesis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2140.