Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus.
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 x 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.


CONCLUSIONS
These findings, indicating the complex genetics of dominant resistance to hepatocarcinogenesis, represent a step toward the identification of the genes underlying this phenotype.
Manenti
Giacomo
G
Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Galvan
Antonella
A
Falvella
F Stefania
FS
Pascale
Rosa M
RM
Spada
Elena
E
Milani
Silvano
S
Gonzalez Neira
Anna
A
Feo
Francesco
F
Dragani
Tommaso A
TA
D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D050687:E2F1 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D007113:Immunity, Innate / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology*; D008126:Lod Score; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse