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 language | English |
|---|---|
| Pages (from-to) | 617-623 |
| Number of pages | 7 |
| Journal | Hepatology |
| Volume | 48 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 2008 |
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ASJC Scopus subject areas
- Hepatology
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Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus. / Manenti, Giacomo; Galvan, Antonella; Falvella, F. Stefania; Pascale, Rosa M.; Spada, Elena; Milani, Silvano; Neira, Anna Gonzalez; Feo, Francesco; Dragani, Tommaso A.
In: Hepatology, Vol. 48, No. 2, 08.2008, p. 617-623.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus
AU - Manenti, Giacomo
AU - Galvan, Antonella
AU - Falvella, F. Stefania
AU - Pascale, Rosa M.
AU - Spada, Elena
AU - Milani, Silvano
AU - Neira, Anna Gonzalez
AU - Feo, Francesco
AU - Dragani, Tommaso A.
PY - 2008/8
Y1 - 2008/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=49649113168&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49649113168&partnerID=8YFLogxK
U2 - 10.1002/hep.22374
DO - 10.1002/hep.22374
M3 - Article
C2 - 18666244
AN - SCOPUS:49649113168
VL - 48
SP - 617
EP - 623
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 2
ER -