Genetic and epigenetic alterations in radiation-induced rat mammary carcinomas

The breast tissue is one of the most susceptible organs to the induction of cancer by ionizing radiation. However, most studies have failed to identify candidate genes for radiation-induced breast carcinogenesis. In the present study, we examined genetic and epigenetic aberrations in rat mammary carcinomas induced by ionizing radiation to identify genes involved in the cancer development.\nRadiation-induced mammary carcinomas (n=22) were obtained from female F1 hybrid rats between mammary cancer susceptible Sprague-Dawley and resistant Copenhagen strains by exposure to 4 Gy of gamma-rays at 7 weeks of age. Genome-wide DNA copy number and DNA methylation status in the carcinomas and normal mammary tissues were analyzed by array comparative genomic hybridization and methylation profiling.\nCopy number losses were identified in small regions of chromosomes 1q52, 2q12-15, 3q31-36 and whole chromosome 5. These included the syntenic regions of human chromosomes, 10q23, 5q11.2, 11p13-14, 1p36 and 8q21-22, where breast cancer susceptible loci and genomic deletions in the breast cancers are frequently reported. The lost region of chromosomes 1-3 and 5 contained breast cancer-related genes such as Pten. Among a total of 15,000 CpG islands in the rat genome, 109 loci were significantly methylated in more than 50% of the carcinomas but not in any of the normal mammary tissues. Among them, we identified 56 candidate hypermethylated protein-coding and noncoding genes. Many of these candidate genes encoded transcription factors, regulating normal development. Gene ontology analysis of these candidate genes revealed that the majority of these genes are involved in cell division, differentiation and development. We also identified a couple of genes as strong candidates for the chromosomes 2q12-15, 3q31-36 and 5q tumor suppressor genes.Keystone Symposia 2013 Epigenetic Marks and Cancer Drug