Poster abstracts

Poster number 29 submitted by Jenna Karras

Signal pathways from genomic instability to tumorigenicity

Jenna R. Karras (Molecular virology, immunology and medical genetics, The Ohio State University), Morgan Schrock (Molecular virology, immunology and medical genetics, The Ohio State University), Satoshi Miuma (Molecular virology, immunology and medical genetics, The Ohio State University), Kay Huebner (Molecular virology, immunology and medical genetics, The Ohio State University)

Abstract:
The fragile FHIT gene, positioned at one of the most active common fragile sites, FRA3B, is a frequently altered gene in preneoplasia and cancer. Loss of the Fhit protein causes an imbalance in thymidine triphosphate pools resulting in spontaneous replication stress that leads to chromosomal aberrations such as aneuploidy, copy number variations and point mutations. Thus, Fhit, which is reduced in expression in most human cancers, is a genome ‘caretaker’ whose loss initiates genome instability in preneoplastic lesions. Preliminary studies show that Fhit knockout mice display a moderately increased frequency of spontaneous tumors and greatly increased susceptibility to carcinogen-induced tumors compared to wild type littermates. Early immortalization and increased copy number variations in Fhit-deficient cells suggests the loss of Fhit is linked to the transformation process. Furthermore, exome sequencing analysis of livers from +/+ and -/- mice, post carcinogen injection, also reveal genomic alterations associated with preneoplastic changes observed in vivo. To understand the early events that lead from Fhit loss to tumorigenicity, we are following the sequence of mutational changes in Fhit -/- and WT kidney cells established from mice in culture. We have identified changes in the p53/p21 pathway as well as epithelial to mesenchymal transition states, a characteristic step for tumor invasion. Thus, Fhit loss-induced genome instability facilitates transformation in vitro.

Keywords: genome instability, common fragile sites