title: Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers.
abstract: FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome "caretaker" required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B.
authors.affiliation: Department of Cancer Biology and Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Karras
authors.forename: Morgan S
authors.initials: MS
authors.lastname: Schrock
authors.forename: Bahadir
authors.initials: B
authors.lastname: Batar
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics; D043283:Chromosome Fragile Sites; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C486071:WWOX protein, human