title: Progressive genomic instability in the FVB/Kras(LA2) 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 Kras(LA2) 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 Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) 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 Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.
authors.affiliation: Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Minh D
authors.initials: MD
authors.lastname: To
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Reyno
authors.initials: R
authors.lastname: Del Rosario
authors.forename: Jeff
authors.initials: J
authors.lastname: Hsu
authors.forename: Graeme
authors.initials: G
authors.lastname: Hodgson
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D042822:Genomic Instability; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)