Progressive Genomic Instability in the FVB/KrasLA2 Mouse Model of Lung Cancer

Abstract

Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the KrasLA2 model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors, and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from KrasLA2 mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the KrasLA2 allele on the inbred FVB/N mouse strain, and in this genetic background there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the KrasLA2 model of lung cancer, and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing

“…Several studies in mouse models have suggested that multiple loci confer selective advantage for whole chromosome gain and loss. For example, Kras-LA2 animals developed spontaneous lung adenomas, and these tumors frequently exhibited whole-chromosome gains of the LA2 -bearing mutant Chr6, whereas focal Kras-LA2 amplifications were uncommon (Sweet-Cordero et al, 2006; To et al, 2011). This led to the speculation that additional oncogenic Chr6 loci are under selection, including other components of Mapk signaling (To et al, 2011).…”

“…For example, Kras-LA2 animals developed spontaneous lung adenomas, and these tumors frequently exhibited whole-chromosome gains of the LA2 -bearing mutant Chr6, whereas focal Kras-LA2 amplifications were uncommon (Sweet-Cordero et al, 2006; To et al, 2011). This led to the speculation that additional oncogenic Chr6 loci are under selection, including other components of Mapk signaling (To et al, 2011). In addition, prior studies of radiation-induced lymphomas from Trp53 +/− animals identified frequent loss of heterozygosity (LOH) at Chr19 and focal deletions involving Pten (Mao et al, 2003).…”

Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer

“…Average staining intensity and percentages of immunoreactive cells were recorded. USP18 IHC was independently performed in paired normal-malignant lung tissues from cyclin E as well as Kras -driven lung cancers in engineered mouse models (24,25). Digital pathology image analysis (Aperio Image Toolbox, Leica Biosystems) determined H-score and measured percentages of stained cells (0–100%) and staining intensity (+0–3).…”

PIK3CAH1047R Accelerates and Enhances KRASG12D-Driven Lung Tumorigenesis

“…Thus additional factors are required to promote the expansion of KRAS-mutated lung epithelial cells. Indeed, KRAS -mediated lung carcinogenesis is reported to require elevated expression of KRAS (9) and/or alterations in the expression/activity of key tumor suppressors such as APC, ARF, INK4A, LKB1, TP53 or PTEN (10–15). Interestingly, despite PI3Kα being a direct effector of KRAS, it is reported that additional activation of PI3′-lipid signaling through IGF1R is required for KRAS-driven lung tumorigenesis (16).…”