Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus

Giacomo Manenti, Antonella Galvan, F. Stefania Falvella, Rosa M. Pascale, Elena Spada, Silvano Milani, Anna Gonzalez Neira, Francesco Feo, Tommaso A. Dragani

Research output: Contribution to journalArticlepeer-review

Abstract

The genome of the BALB/c mouse strain provides alleles that dominantly inhibit hepatocellular tumor development in F1 crosses with the highly hepatocarcinogenesis-susceptible C3H/He strain. Genome-wide linkage analysis using a 1536-single-nucleotide polymorphism array in a (C3H/He × BALB/c)F2 intercross population treated with urethane to induce hepatocellular tumor development revealed a locus with a major role in the resistance to hepatocarcinogenesis. This locus, designated hepatocarcinogen resistance 3 (Hpcr3) and mapping to central chromosome 15, showed a linkage at LOD score = 16.52 and accounted for 40% of the phenotypical variance. The BALB/c-derived allele at Hpcr3 reduced tumor-occupied area of the liver up to 25-fold, in a semidominant way. Additional minor loci were mapped to chromosomes 1, 10, and 18. A gene expression profile of normal adult mouse liver showed a significant association with susceptibility of BALB/c, C3H/He, and F1 mice to hepatocarcinogenesis and identified the genes expressed in the Hpcr3 locus region; moreover, this analysis implicated the E2F1 pathway in the modulation of the phenotype susceptibility to hepatocarcinogenesis. Conclusion: These findings, indicating the complex genetics of dominant resistance to hepatocarcinogenesis, represent a step toward the identification of the genes underlying this phenotype.

Original languageEnglish
Pages (from-to)617-623
Number of pages7
JournalHepatology
Volume48
Issue number2
DOIs
Publication statusPublished - Aug 2008

ASJC Scopus subject areas

  • Hepatology

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