Muir-Torre-like syndrome in Fhit deficient mice

Abstract

The invention provides nonhuman transgenic animals with a disrupted FHIT gene. The invention further provides transgenic mice in which one or both Fhit alleles have been inactivated. Preferably, the Fhit-deficient mice develop multiple tumors of both visceral and sebaceous origin, similar to those of Muir-Torre familial cancer syndrome. The present invention further relates to the generation of these transgenic mice and their use as model systems to study the effects of carcinogenic agents in promoting clonal expansion of neoplastic cells in cancers, preferably gastrointestinal cancers of which Muir-Torre syndrome is a subset. The invention further relates to testing therapeutic agents for their efficacy in the prevention and treatment of cancer, preferably gastrointestinal cancer.

1 . An embryonic stem cell containing a disruption in a FHIT gene, wherein said disruption affects one or more exons of said FHIT gene.  
     
     
         2 - 22 . (canceled)  
     
     
         23 . A transgenic non-human animal having a genome containing a disruption in the FHIT gene of said animal.  
     
     
         24 . The transgenic non-human animal of  claim 23 , wherein said disruption comprises a termination codon in an exon of the FHIT gene.  
     
     
         25 . The transgenic non-human animal of  claim 23 , wherein said disruption in the FHIT gene is selected from the group consisting of an insertion, a deletion, a substitution, a rearrangement, a point mutation, an ablation of a gene regulatory sequence and a combination thereof.  
     
     
         26 . The transgenic non-human animal of  claim 23 , wherein said disruption in the FHIT gene is a homozygous disruption.  
     
     
         27 . The transgenic non-human animal of  claim 23 , wherein said disruption in the FHIT gene is a heterozygous disruption.  
     
     
         28 . The transgenic non-human animal of  claim 23 , wherein said disruption in the FHIT gene is present in both germline and somatic cells.  
     
     
         29 . The transgenic non-human animal of  claim 23 , wherein said animal has increased susceptibility to visceral and sebaceous tumors relative to a FHIT +/+ animal.  
     
     
         30 . The transgenic non-human animal of  claim 23 , wherein said animal exhibits increased tumor formation upon being exposed to N-nitrosomethylbenzlamine relative to a FHIT +/+ animal that has been exposed to N-nitrosomethylbenzlamine.  
     
     
         31 . The transgenic non-human animal of  claim 23 , wherein said animal is a mammal.  
     
     
         32 . The transgenic non-human animal of  claim 31 , wherein said mammal is a mouse.  
     
     
         33 . A transgenic non-human animal, wherein said animal is chimeric for a disruption in the FHIT gene of said animal.  
     
     
         34 . The transgenic non-human animal of  claim 33 , wherein said animal has increased susceptibility to visceral and sebaceous tumors relative to a FHIT +/+ non-human animal.  
     
     
         35 . The transgenic non-human animal of  claim 33 , wherein said animal exhibits increased tumor formation upon being exposed to N-nitrosomethylbenzlamine relative to a FHIT +/+non-human animal that has been exposed to N-nitrosomethylbenzlamine.  
     
     
         36 . The transgenic non-human animal of  claim 33 , wherein said animal is a mammal.  
     
     
         37 . The transgenic non-human animal of  claim 36 , wherein said mammal is a mouse.  
     
     
         38 . The transgenic non-human animal of  claim 33 , wherein said disruption comprises a termination codon in an exon of the FHIT gene.  
     
     
         39 . The transgenic non-human animal of  claim 33 , wherein said disruption in the FHIT gene is selected from the group consisting of an insertion, a deletion, a substitution, a rearrangement, a point mutation, an ablation of a gene regulatory sequence and a combination thereof.  
     
     
         40 . A cell culture prepared with cells from the transgenic non-human animal of  claim 23 .  
     
     
         41 . A method of testing carcinogenicity of a molecule, comprising: 
 (a) administering said molecule to the transgenic non-human animal of  claim 23;  and    (b) comparing the rate of tumor formation in said transgenic non-human animal with a control non-human animal of the same genotype to which said molecule is not administered;    wherein an increased rate of tumor formation in said transgenic non-human animal following administration of said test molecule, as compared to the rate of tumor formation in said control non-human animal, is indicative that said molecule is a carcinogen.    
     
     
         42 . A method of testing the therapeutic efficacy of a molecule in treating and/or preventing cancer comprising: 
 (a) administering said molecule to the transgenic non-human animal of  claim 23;  and    (b) comparing the rate of tumor formation in said transgenic non-human animal with a control non-human animal of the same genotype to which said molecule is not administered;    wherein a reduced rate of tumor formation in said transgenic non-human animal following administration of said molecule, as compared to the rate of tumor formation in said control non-human animal, is indicative that said molecule has therapeutic efficacy for treating and/or preventing cancer.    
     
     
         43 . The method of  claim 42 , wherein said cancer is a gastrointestinal cancer.  
     
     
         44 . The method of  claim 42 , wherein said cancer is a Muir-Torre Syndrome-related cancer.  
     
     
         45 . The method of  claim 42 , wherein said cancer is hereditary non-polyposis colorectal cancer.