Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.
Genetic background affects susceptibility to pancreatic ductal adenocarcinoma 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 preinvasive 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.
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Tonia C
TC
Jorgenson
Bret R
BR
Williams
Allyson
A
Wendland
Andrea
A
Bilger
Eric P
EP
Sandgren
Norman R
NR
Drinkwater
D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics; D018450:Disease Progression; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins