Genetic Analyses of pancreatic cancer susceptibility in Ela-KRASG12D transgenic mice.

摘要

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma (PDAC) in Ela-KRASG12D mice. Through linkage analysis of crosses between C57BL/6J (B6), DBA/2J (D2), and BALB/cJ (BALB) inbred strains of mice and resistant FVB-Tg(Ela-KRAS G12D), we identified three loci that affect lesion multiplicity. Markers on Chromosomes 2 segregated with multiplicity in all three strains (combined LODw score of ∼ 13), and this locus was designated Prs1 (Pancreatic ras susceptibility). A locus on Chromosome 4, designated Prs2, was identified in crosses between FVB transgenic mice and B6 or BALB mice (combined LODw score of ∼ 8). A marker on Chromosome 12 segregated with multiplicity in BALBxFVB- Tg(Ela-KRASG12D) and was designated Prs3 (LODw ∼ 2.5). Our findings provide evidence that regions of Chromosomes 2, 4, and 12 contain loci that influence the development of lesions initiated by oncogenic KRAS.;We constructed consomics to investigate the effects of the Ela-KRAS G12D transgene on a non-FVB background. B6-Y -Tg(Ela-KRASG12D) and BALB-Y FVB-Tg(Ela-KRASG12D) consomics, develop ∼ 4-7-fold (B6) and ∼ 7-10-fold (BALB) more lesions than FVB-Tg(Ela-KRASG12D ) mice between 6 and 12 months of age. This susceptibility relative to FVB-Tg(Ela-KRASG12D) is evidence that they carry alleles that affect pancreatic lesion multiplicity.;Congenic lines carrying susceptibility and/or resistance loci for Prs1 and Prs2 were created. The two most susceptible congenic lines carried segments of B6 for Prs1 and BALB for Prs2 on an FVB background, are 2.9-4.1 and 3.1-5.6-fold more susceptible, respectively, than FVB at 6, 9, and 12 months of age. The region on Chromosome 2 containing Prs1 has been limited to a region from 91.8 to 162 MB, while Prs2 has been limited to 45.7 to 106.8 MB on Chromosome 4. These congenic lines have confirmed the linkage of pancreatic cancer susceptibility modifiers to Prsl and Prs2 and show that these loci act independently.;Consomic and congenic mice carrying B6 and BALB alleles develop more advanced mouse pancreatic intraepithelial neoplasia (mPanIN) lesions more frequently than FVB-Tg(Ela-KRASG12D). Furthermore, by 12 months of age 10 percent of BALB-Y FVB-Tg(Ela-KRASG12D) mice develop invasive carcinomas. This result suggests that the B6 Prs1 and BALB Prs2 alleles modify pancreatic cancer progression.