title: Exome-wide single-base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse.
abstract: Loss of expression of Fhit, a tumor suppressor and genome caretaker, occurs in preneoplastic lesions during development of many human cancers. Furthermore, Fhit-deficient mouse models are exquisitely susceptible to carcinogen induction of cancers of the lung and forestomach. Due to absence of Fhit genome caretaker function, cultured cells and tissues of the constitutive Fhit knockout strain develop chromosome aneuploidy and allele copy number gains and losses and we hypothesized that Fhit-deficient cells would also develop point mutations. On analysis of whole exome sequences of Fhit-deficient tissues and cultured cells, we found 300 to >1000 single-base substitutions associated with Fhit loss in the 2% of the genome included in exomes, relative to the C57Bl6 reference genome. The mutation signature is characterized by increased C>T and T>C mutations, similar to the "age at diagnosis" signature identified in human cancers. The Fhit-deficiency mutation signature also resembles a C>T and T>C mutation signature reported for human papillary kidney cancers and a similar signature recently reported for esophageal and bladder cancers, cancers that are frequently Fhit deficient. The increase in T>C mutations in -/- exomes may be due to dNTP imbalance, particularly in thymidine triphosphate, resulting from decreased expression of thymidine kinase 1 in Fhit-deficient cells. Fhit-deficient kidney cells that survived in vitro dimethylbenz(a)anthracene treatment additionally showed increased T>A mutations, a signature generated by treatment with this carcinogen, suggesting that these T>A transversions may be evidence of carcinogen-induced preneoplastic changes.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Paisie
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Morgan S
authors.initials: MS
authors.lastname: Schrock
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Karras
authors.affiliation: Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miuma
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Iman M
authors.initials: IM
authors.lastname: Ouda
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Waters
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Saldivar
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Columbus, Ohio, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D002273:Carcinogens; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase
keywords: Constitutive knockout mouse strains; genome instability; mouse cancer models; mutation signatures; whole exome sequencing