Changes in copy-number of specific genes contributes to the development of human neoplasia. Comparative genomic hybridization to cDNA microarrays (array-CGH) is an emerging functional genomic technique for detecting these genetic changes. Using array-CGH we have obtained preliminary evidence of widespread gene amplification in multiple, clustered loci present in thyroid epithelial cancers from children who were exposed to ionizing radiation from the Chernobyl accident, but not in comparable thyroid epithelial cancers from US children lacking known radiation exposure. We hypothesize the existence of a pool of sites in the genome which respond to radiation by low level gene amplification. To extend our initial findings, and test our hypothesis, we will collect and analyze new thyroid cancer cases from the same population. This fresh material will allow us to obtain data regarding the tumor-specificity of radiation-associated gene copy number change in the thyroid, the relationship of age at exposure, tumor latency and estimated radiation dose on gene copy number change. Taking advantage of the human genome sequence, we will map relative sensitivity of these apparent radiation effects within the genome. Additionally we will attempt to enhance the array CGH techniques by exploiting the reported presence of long palindromes in tumor-associated amplicons. Probes enriched for long palindromes will be compared with conventional DNA fragments in array analysis. A new human BAC array will be used selectively to supplement data obtained from cDNA arrays to better define amplicons where needed. Finally, by means of these newly acquired patient samples, we will exploit the power of microarray technology to explore the relationship of gene copy change to gene expression levels, and to seek candidate oncogenes consistently over expressed in these thyroid cancers. Completion of this project will enhance array CGH as a technique for detecting and mapping changes in gene copy-number on a genome-wide scale, and provide a more complete description of mechanisms underlying radiation-induce thyroid neoplasia.
| Kimmel, Robert R; Agnani, Shivali; Yang, Yin et al. (2008) DNA copy-number instability in low-dose gamma-irradiated TK6 lymphoblastoid clones. Radiat Res 169:259-69 |
| Kimmel, Robert R; Zhao, Lue Ping; Nguyen, Doan et al. (2006) Microarray comparative genomic hybridization reveals genome-wide patterns of DNA gains and losses in post-Chernobyl thyroid cancer. Radiat Res 166:519-31 |
| Neiman, P E; Kimmel, R; Icreverzi, A et al. (2006) Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius. Oncogene 25:6325-35 |
