Exome-wide single-base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse

Cancer Science
Carolyn A PaisieKay Huebner

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...Continue Reading

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Citations

Aug 16, 2016·Cancer Science·Jenna R KarrasKay Huebner
Oct 25, 2016·Advances in Biological Regulation·Morgan S SchrockKay Huebner
Sep 23, 2018·Genes, Chromosomes & Cancer·Joshua C Saldivar, Dongju Park
Aug 15, 2018·American Journal of Respiratory and Critical Care Medicine·Svenja Dannewitz ProssedaEdda Spiekerkoetter
Jan 19, 2019·Endocrine Reviews·Andrea Mafficini, Aldo Scarpa

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Datasets Mentioned

BETA
SRP046420
PRJNA260539

Methods Mentioned

BETA
exome sequencing
PCR
deamination

Software Mentioned

UCSC genome browser
EdgeBio
BCFtools
JAX

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