Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.
Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.
复制标题
DOI：
10.1158/0008-5472.can-09-3980
复制
发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Drinkwater NR
中科院分区：
文献类型：
--
作者：
Jorgenson TC;Williams BR;Wendland A;Bilger A;Sandgren EP;Drinkwater NR
遗传背景影响Ela-KRASG 12 D小鼠模型中胰腺导管腺癌（PDAC）的易感性。在该模型中，在FVB/NTac（FVB）背景[FVB-Tg（Ela-KRASG 12 D）]下，胰腺腺泡细胞中的弹性蛋白酶启动子驱动KRAS癌基因表达，转基因携带在Y染色体上。通过C57 BL/6 J（B6）、BALB/cJ（BALB）和DBA/2 J（D2）近交系小鼠与耐药FVB-Tg（Ela-KRASG 12 D）之间的杂交的连锁分析，我们已经确定了影响平均侵袭前病变多样性的6个易感基因座。染色体2上的标记在所有三个菌株中以高肿瘤多样性分离;这些位点被命名为Prsq 1 -3（胰腺癌易感性数量性状位点1-3;组合F2和N2 LODW分别为6.0、4.1和2.7）。在FVB转基因小鼠和B6或BALB小鼠之间的杂交中鉴定了染色体4上的易感基因座，命名为Prsq 4和Prsq 5（组合F2和N2的LODW分别为3.6和2.9）。在BALB×FVB-Tg（Ela-KRASG 12 D）杂交中，12号染色体上的标记物与肿瘤多样性分离，并被命名为Prsq 6（LODW ~ 2.5）。B6-Chr YFVB-Tg（Ela-KRASG 12 D）和BALB-Chr YFVB-Tg（Ela-KRASG 12 D）同源体在FVB Y染色体上携带KRAS转基因，在其他近交系B6或BALB背景下，比FVB-Tg（Ela-KRASG 12 D）小鼠发生约4倍（B6）和约10倍（BALB）的病变。到12月龄时，10%的BALB-Chr YFVB-Tg（Ela-KRASG 12 D）小鼠发展为浸润性癌。我们的研究结果提供的证据表明，染色体2，4和12的区域影响胰腺肿瘤的发展和进展发起的致癌等位基因的KRAS在小鼠中。
Genetic background affects susceptibility to pancreatic ductal adenocarcinoma (PDAC) in the Ela-KRASG12D 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-KRASG12D)] 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-KRASG12D), 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 LODW 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 LODW 3.6 and 2.9, respectively). A marker on Chromosome 12 segregated with tumor multiplicity in a BALB×FVB-Tg(Ela-KRASG12D) cross and was designated Prsq6 (LODW ~ 2.5). B6-Chr YFVB-Tg(Ela-KRASG12D) and BALB-Chr YFVB-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-KRASG12D) mice. By 12 months of age, 10% of BALB-Chr YFVB-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.