Reference SummaryMcGlynn KA, Cancer Res 2003 Aug 1;63(15):4594-601

Title

 Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans.

Authors

 McGlynn KA; Hunter K; LeVoyer T; Roush J; Wise P; Michielli RA; Shen FM; Evans AA; London WT; Buetow KH

Journal

 Cancer Res

Volume

 63

Issue

 15

Year

 2003

Pages

 4594-601

Abstract

 The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B(1) (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis.

Links

 J:85696 – MGI References
12907637 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

26.67
C57BL/6J Liver hepatocellular carcinoma
  • tricaprylin (trioctanoin)
 Liver

0
DBA/2J Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

90
DBA/2J Liver hepatocellular carcinoma
  • tricaprylin (trioctanoin)
 Liver

0
B6.129S2-Trp53tm1Tyj/J Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

0
B6.129S2-Trp53tm1Tyj/J Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

10
C57BL/6J-Tg(Alb1HBV)44Bri/J Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

100
C57BL/6J-Tg(Alb1HBV)44Bri Trp53tm1Tyj/+ Liver hepatocellular carcinoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

100
B6.129S2-Trp53tm1Tyj/J Lymphoid tissue lymphoma
  • aflatoxin B1 (AFB1) (AFB1)
 Liver

100