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      Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof of principle study with colorectal cancer

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          Abstract

          Herein we report a proof of principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human- and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes ( RASA3, NUPL1, DENND5A, and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

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          Most cited references46

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          Chronic myeloid leukemia.

          C Sawyers (1999)
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            Adaptation of core mechanisms to generate cell polarity.

            Cell polarity is defined as asymmetry in cell shape, protein distributions and cell functions. It is characteristic of single-cell organisms, including yeast and bacteria, and cells in tissues of multi-cell organisms such as epithelia in worms, flies and mammals. This diversity raises several questions: do different cell types use different mechanisms to generate polarity, how is polarity signalled, how do cells react to that signal, and how is structural polarity translated into specialized functions? Analysis of evolutionarily diverse cell types reveals that cell-surface landmarks adapt core pathways for cytoskeleton assembly and protein transport to generate cell polarity.
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              Dog models of naturally occurring cancer.

              Studies using dogs provide an ideal solution to the gap in animal models for natural disease and translational medicine. This is evidenced by approximately 400 inherited disorders being characterized in domesticated dogs, most of which are relevant to humans. There are several hundred isolated populations of dogs (breeds) and each has a vastly reduced genetic variation compared with humans; this simplifies disease mapping and pharmacogenomics. Dogs age five- to eight-fold faster than do humans, share environments with their owners, are usually kept until old age and receive a high level of health care. Farseeing investigators recognized this potential and, over the past decade, have developed the necessary tools and infrastructure to utilize this powerful model of human disease, including the sequencing of the dog genome in 2005. Here, we review the nascent convergence of genetic and translational canine models of spontaneous disease, focusing on cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                13 February 2014
                18 February 2013
                13 February 2014
                13 August 2014
                : 33
                : 7
                : 814-822
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA
                [2 ]Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD.
                Author notes
                [* ]Address correspondence to: Shaying Zhao, PhD Associate Professor Department of Biochemistry and Molecular Biology, Institute of Bioinformatics University of Georgia B304B Life Sciences Building, 120 Green Street, Athens, GA 30602-7229 szhao@ 123456bmb.uga.edu , 706-542-9147 Tel, 706-542-1738 Fax
                Article
                NIHMS550055
                10.1038/onc.2013.17
                3932186
                23416983
                96a205e3-65f1-4e04-ba69-e5017d40f885

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA128613 || CA
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: P01 GM085354 || GM
                Categories
                Article

                Oncology & Radiotherapy
                crc driver-passenger distinction,sporadic canine crcs,human-dog comparison,epithelial cell apicobasal polarity,genomic amplifications/deletions

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