Genetic changes as biomarkers of mouse lung adenocarcinoma: comparison to human.
Sargent-LM; Ensell-MX; Baldwin-KT; Kashon-ML; Jefferson-AM; Lowry-DT; Ostvoid-A-C; Senft-JR; Johnson-RC; Tyson-FL; Reynolds-SH
2007 Toxicology and Risk Assessment Conference, Emerging Issues and Challenges in Risk Assessment, April 23-26, 2007, Cincinnati, Ohio. 2007 Apr; :47
The incidence of adenocarcinoma of the lung is increasing in the United States, however, the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the intense study of mouse models for lung cancer. We used Spectral Karyotyping (SKY), mapping with fluorescently labeled genomic clones (FISH), comparative genomic hybridization (CGH) arrays, gene expression arrays, Western immunoblot and real time polymerase chain reaction (PCR) to analyze 15 early passage mouse lung adenocarcinoma cell strains and nine pairs of high-invasive and low-invasive mouse lung adenocarcinoma tumor cell strain pairs to detect genetic biomarkers associated with mouse lung adenocarcinoma phenotype and tumor invasion. The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high-invasive phenotype. The amplification of chromosome 1 at band C4 and E1/2- H1 were the most significant chromosomal changes in the high-invasive cell strains. Mapping with FISH and CGH array further narrowed the minimum region of duplication of chromosome 1 to 40 centimorgans (cM) and 71-82 cM. Within these minimal regions of chromosome 1 duplication, analysis of gene expression arrays and confirmation by real time PCR demonstrated increased expression of COX-2, Translin (TB-RBP), DYRK3, NUCKS and Tubulin-a4 genes in the high-invasive cell strains. Elevated expression and copy number of these genes, which are involved in inflammation, cell movement, proliferation, inhibition of apoptosis, mitotic spindle integrity and telomere elongation, were associated with an invasive phenotype and are potential genetic biomarkers of lung carcinogenesis. The amplified regions of chromosome 1 contain mouse lung susceptibility loci. The homologous linkage groups on human chromosomes 1 q32-41 and 2q are likewise altered in invasive human lung cancer. Increased copy number and expression of genes on mouse chromosome 1 may playa functional role in lung cancer development and may aid in identifying unique lung cancer biomarkers as well as susceptibility genes in mouse and human.
Toxicology; Risk-analysis; Biomarkers; Lung-cancer; Lung-disorders; Respiratory-system-disorders; Pulmonary-system-disorders; Models; Gene-mutation
Abstract; Conference/Symposia Proceedings
2007 Toxicology and Risk Assessment Conference, Emerging Issues and Challenges in Risk Assessment, April 23-26, 2007, Cincinnati, Ohio