Collaborating genomic, transcriptomic and microbiomic alterations lead to canine extreme intestinal polyposis

// Jin Wang 1 , Tianfang Wang 1 , Micah A. Bishop 3 , John F. Edwards 2 , Hang Yin 1 , Stephen Dalton 1 , Laura K. Bryan 2 and Shaying Zhao 1 1 Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA 2 Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas AM germline and somatic mutation; MYC network activation; microbiome; B. uniformis and redox Received: January 22, 2018      Accepted: June 01, 2018      Published: June 26, 2018 ABSTRACT Extreme intestinal polyposis in pet dogs has not yet been reported in literature. We identified a dog patient who developed numerous intestinal polyps, with the severity resembling human classic familial adenomatous polyposis (FAP), except the jejunum-ileum junction being the most polyp-dense. We investigated this dog, in comparison with 22 other dogs with spontaneous intestinal tumors but no severe polyposis, and with numerous published human cancers. We found, not APC mutation, but three other alteration pathways as likely reasons of this canine extreme polyposis. First, somatic truncation mutation W411X of FBXW7, a component of an E3 ubiquitin ligase, over-activates MYC and cell cycle-promoting network, accelerating crypt cell proliferation. Second, genes of protein trafficking and localization are downregulated, likely associated with germline mutation G406D of STAMBPL1, a K63-deubiquitinase, and MYC network activation. This inhibits epithelial apical-basolateral polarity establishment, preventing crypt cell differentiation. Third, Bacteroides uniformis , a commensal gut anaerobe, thrives and expresses abundantly thioredoxin and nitroreductase. These bacterial products could reduce oxidative stress linked to host germline mutation R51X of CYB5RL, a cytochrome b5 reductase homologue, decreasing cell death. Our work emphasizes the close collaboration of alterations across the genome, transcriptome and microbiome in promoting tumorigenesis.