Aflatoxin B1 and/or hepatitis B virus induced tumor spectrum in a genetically engineered hepatitis B virus expression and Trp53 haploinsufficient mouse model system for hepatocarcinogenesis.
The authors investigated the spectrum of tumors and Trp53 mutations in genetically engineered models using the FVB/N mouse that expressed the hepatitis B virus genome and/or carried a Trp53 null and wildtype allele and/or were exposed to aflatoxin B1. Liver tumor incidence was increased when all three risk factors were present. Without aflatoxin B1 exposure, neither Trp53 haploinsufficiency nor HBV expression affected liver tumor development. Liver tumor prevalence increased with aflatoxin B1 exposure (p < .001), as thirteen of fourteen mice with liver tumors were initiated with aflatoxin B1. Liver tumors were more frequent in males (12/190) than females (2/170). Seventy-three mice developed sarcomas. Trp53 haploinsufficiency was associated with increased sarcoma incidence in males and females (p < .001). In Trp53 haploinsufficient mice, the HBV transgene increased the risk of sarcoma in males and females (p < .001). Lymphoma was significantly increased in Trp53 haploinsufficient FVB/N mice. There was no loss of heterozygosity at the wildtype Trp53 locus in twenty-five sarcomas or four hepatocellular tumors examined. No mutations were identified in the mRNA (exons 2-11) of Trp53 in six liver neoplasms or twenty-four sarcomas. In this model system, HBV expression affected only hepatocellular neoplasia in association with both aflatoxin B1 initiation and p53 haploinsufficiency.
Cullen
John M
JM
College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA. john_cullen@ncsu.edu
Brown
Danielle L
DL
Kissling
Grace E
GE
Foley
Julie F
JF
Rizzo
Jennifer
J
Marion
Patricia L
PL
Parron
Vandy I
VI
French
John E
JE
D016604:Aflatoxin B1 / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005818:Genetic Engineering / Q000009:adverse effects; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D012737:Sex Factors; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D006514:Hepatitis B Surface Antigens; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D016604:Aflatoxin B1