title: Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.
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, although 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.
authors: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA.
authors: J
authors: J
authors: Tang
authors: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA.
authors: Y
authors: Y
authors: Li
authors: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA.
authors: K
authors: K
authors: Lyon
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA.
authors: J
authors: J
authors: Camps
authors: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA.
authors: S
authors: S
authors: Dalton
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA.
authors: T
authors: T
authors: Ried
authors: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA.
authors: S
authors: S
authors: Zhao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics*; D004285:Dogs; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors; D045325:HCT116 Cells; D006801:Humans; D058977:Molecular Sequence Annotation; D017239:Paclitaxel / Q000494:pharmacology; D010865:Pilot Projects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C574860:DENND5A protein, human; D020662:Guanine Nucleotide Exchange Factors; D018160:Receptors, Cytoplasmic and Nuclear; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; D020691:rab GTP-Binding Proteins; D017239:Paclitaxel