Identification of Susceptibility Loci in a Mouse Model of K-rasG12D-driven Pancreatic Cancer

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma (PDAC) in the Ela-KRAS G12D mouse model. In this model, KRAS oncogene expression is driven by an Elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB- Tg(Ela-KRAS G12D ) ] with the transgene carried on the Y Chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB- Tg ( Ela-KRAS G12D ) , we have identified six susceptibility loci that affect mean pre-invasive lesion multiplicity. Markers on Chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 ( Pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LOD W 6.0, 4.1, and 2.7, respectively). Susceptibility loci on Chromosome 4, designated Prsq4 and Prsq5 , were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LOD W 3.6 and 2.9, respectively). A marker on Chromosome 12 segregated with tumor multiplicity in a BALB×FVB- Tg ( Ela-KRAS G12D ) cross and was designated Prsq6 (LOD W ~ 2.5). B6-Chr Y FVB- Tg(Ela-KRASG12D) and BALB-Chr Y FVB- Tg(Ela-KRASG12D) consomics, which carry the KRAS transgene on the FVB Y Chromosome on an otherwise inbred B6 or BALB background, developed ~4-fold (B6) and ~10-fold (BALB) more lesions than FVB- Tg(Ela-KRAS G12D ) mice. By 12 months of age, 10% of BALB-Chr Y FVB- Tg(Ela-KRASG12D) mice developed invasive carcinomas. Our findings provide evidence that regions of Chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice.