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      Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

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          Abstract

          The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers.

          Author Summary

          Cancer is essentially a genetic disease, caused by serial genetic changes including point mutations and chromosome number abnormalities. The latter leads to copy number alterations of many genes. While there are usually thousands of these genetic changes in a given tumor, only a small fraction likely contribute to cancer development. One of the major challenges is to distinguish these cancer “driver” genes from “passenger” mutations that do not contribute to the cancer phenotype. In particular, identifying the driver genes on entire chromosomes that are frequently gained or lost in tumors remains a recalcitrant problem as these alterations contain so many genes. We demonstrate that, because the chromosomal location of genes is highly scrambled between zebrafish and human, the number of passenger genes can be dramatically reduced by comparing the genes in copy number alterations found in zebrafish and human tumors. Thus, our approach dramatically narrows down the list of candidate cancer drivers, and can accelerate discovery of novel cancer drivers and pathways that could inform future targeted therapy and personalized medicine.

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          Most cited references70

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          Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.

          Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
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            A faster circular binary segmentation algorithm for the analysis of array CGH data.

            Array CGH technologies enable the simultaneous measurement of DNA copy number for thousands of sites on a genome. We developed the circular binary segmentation (CBS) algorithm to divide the genome into regions of equal copy number. The algorithm tests for change-points using a maximal t-statistic with a permutation reference distribution to obtain the corresponding P-value. The number of computations required for the maximal test statistic is O(N2), where N is the number of markers. This makes the full permutation approach computationally prohibitive for the newer arrays that contain tens of thousands markers and highlights the need for a faster algorithm. We present a hybrid approach to obtain the P-value of the test statistic in linear time. We also introduce a rule for stopping early when there is strong evidence for the presence of a change. We show through simulations that the hybrid approach provides a substantial gain in speed with only a negligible loss in accuracy and that the stopping rule further increases speed. We also present the analyses of array CGH data from breast cancer cell lines to show the impact of the new approaches on the analysis of real data. An R version of the CBS algorithm has been implemented in the "DNAcopy" package of the Bioconductor project. The proposed hybrid method for the P-value is available in version 1.2.1 or higher and the stopping rule for declaring a change early is available in version 1.5.1 or higher.
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              Characterizing the cancer genome in lung adenocarcinoma.

              Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2013
                August 2013
                29 August 2013
                : 9
                : 8
                : e1003734
                Affiliations
                [1 ]David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America
                [2 ]Bioinformatics Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany
                [3 ]Department of Human Genetics, Catholic University Leuven, Leuven, Belgium
                [4 ]Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America
                University of Washington, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GZ SH AA EB EL NH JAL. Performed the experiments: GZ SH AA CAW EB SF. Analyzed the data: GZ SH AA CAW EB NH JAL. Contributed reagents/materials/analysis tools: JMC JHP. Wrote the paper: GZ SH AA NH JAL.

                Article
                PGENETICS-D-13-00798
                10.1371/journal.pgen.1003734
                3757083
                24009526
                6d13e21d-7e45-4e9a-a797-53fd3b3e0d5d
                Copyright @ 2013

                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.

                History
                : 20 March 2013
                : 5 July 2013
                Page count
                Pages: 13
                Funding
                This work was supported by a grant from Arthur C. Merrill, a grant from the Kathy and Curt Marble Cancer Research Fund, and National Institutes of Health grants CA106416, ROI RR020833, and 1F32GM095213-01. JAL is a Ludwig Scholar at MIT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Genetics
                Genetics

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