Hcs8^CBA/J
QTL Variant Detail

Summary

• QTL variant: Hcs8^CBA/J
• Name: hepatocarcinogenesis susceptibility 8; CBA/J
• MGI ID: MGI:3046654
• QTL: Hcs8 Location: unknown Genetic Position: Chr1, Syntenic

Variant origin

• Strain of Specimen: CBA/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers hepatocarcinogenesis susceptibility compared to C57BL/6J. (J:91132)
• Inheritance: Dominant

Notes

CBA/J-derived alleles confer increased incidence of liver tumors with dominant inheritance at this locus.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:91132

A previously identified QTL for liver cancer susceptibility, Hcs7, was detected in genome scans of two intercrosses and two backcrosses involving C57BL/6J, CBA/J, and C3H/HeJ. Parental strains CBA/J and C3H/HeJ are susceptible to spontaneous and induced hepatocarcinoma compared to parental strain C57BL/6J.

53 (C57BL/6J x C3H/HeJ)F1 x C57BL/6J animals were injected with N,N-diethylnitrosamine (DEN) at 12 days of age and screened for 107 polymorphic markers at a resolution of 15 cM. Significant linkage mapped to 88 cM on mouse Chromosome 1 near D1Mit15 (LOD=3.06). Heterozygosity at D1Mit15 confers 2-fold increased tumor incidence compared to C57BL/6J homozygotes. This locus is Hcs7. Next, 53 (C57BL/6J x C3H/HeJ)F2 animals were analyzed in the same fashion and linkage to liver tumor susceptibility mapped to 63 cM near D1Mit13 (LOD=2.85). Heterozygosity confers a 3-fold increase in liver tumor incidence and homozygosity for C3H/HeJ-derived alleles confers a 5-fold increase in liver tumor incidence at D1Mit13.

Linkage analysis was also performed on 53 (C57BL/6J x CBA/J)F1 x C57BL/6J backcross animals and 95 (C57BL/6J x CBA/J)F2 intercross animals using 74 microsatellite markers at a resolution of 20 cM. Again, a locus mapped to distal mouse Chromosome 1 at 93 cM near D1Mit113 (LOD=3.29) in the backcross, and to 82 cM near D1Mit33 (LOD=3.21) in the intercross. CBA/J-derived alleles confer increased incidence of liver tumors with dominant inheritance at this locus.

10.16.2015 Curator Note: Because Hcs7 was originally mapped using the C57BL/6J x C3H/HeJ population, which differs from the C57BL/6J x CBA/J population, we consider this second cross a separate mapping experiment and have named this QTL, mapping to Chr 1 near D1Mit113 with a LOD=3.29, Hcs8 .

Two congenic lines were constructed carrying C3H/HeJ-derived DNA or C57BR/cdJ-derived DNA from D1Mit5 (32.8 cM) to Tgfbm2 (106.3 cM) on a C57BL/6J genetic background. Parental strain C57BR/cdJ is up to 50-fold more susceptible to liver tumors compared to C57BL/6J.

B6.C3-(D1Mit5-Tgfbm2) congenic males exhibit a 13-fold increase in liver tumor susceptibility and females exhibit a 4-fold increase in liver tumor susceptibility.

B6.BR-(D1Mit5-Tgfbm2) congenic males exhibit a 6-fold increase in liver tumor susceptibility while females exhibit a 3-fold increase in liver tumor susceptibility. The C3H/HeJ and the C57BR/cdJ alleles of Hcs7 and of Hcs9 appear to have a semidominant mode of inheritance in females and a dominant mode of inheritance in males.

10.16.2015 Curators Note: Because the mice used in the B6.BR-(D1Mit5-Tgfbm2) congenic map study differ from those used to map both Hcs7 and Hcs8 we have also given the QTL identified in this congenic study a unique symbol, Hcs9.

Hcs7 is syntenic to human Chromosome 1q21-q23. Potential candidate genes mapping near Hcs7 include Pbx1 (88.1 cM), Rgs4 (86.5 cM), Rgs5 (86.5), Dedd, Ddr2 (90 cM), Atf6, and Fasl (85 cM). Hsc7 colocalizes with Hcif2, a hepatocarcinoma susceptibility QTL near D1Mit33 that wasidentifiedin C57BL/6J and C57BR/cdJ mice. Authors offer the possibility that Hcs7 and Hcif2 may be the same QTL.

References

• Original: J:91132 Bilger A, et al., A potent modifier of liver cancer risk on distal mouse chromosome 1: linkage analysis and characterization of congenic lines. Genetics. 2004 Jun;167(2):859-66
• All: 1 reference(s)