S-Driven Pancreatic Cancer

Downlo etic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS mouse . In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the panon an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS)] with the transgene carried on the Y chroe. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) strains of mice and resistant FVB-Tg(Ela-KRAS), we have identified six susceptibility loci that affect preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; comF2 and N2 LODW, 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined N2 LODW, 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in B × FVB-Tg(Ela-KRAS) cross and was designated Prsq6 (LODW, ∼2.5). B6-Chr Y and Chr Y consomics, which carry the KRAS transgene on the FVB Y chromosome on an ise inbred B6 or BALB background, developed ∼4-fold (B6) and ∼10-fold (BALB) more lesions than g(Ela-KRAS) mice. By 12 months of age, 10% of BALB-Chr Y mice developed invarcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the develsive ca opment and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice. Cancer Res; 70(21); 8398–406. ©2010 AACR.