Abstract
X-ray irradiation at postnatal day 1 significantly increased the incidence of medulloblastoma in Ptch1 heterozygous mice on C3B6F1 genetic background in a dose-dependent fashion. Spontaneously developed tumors showed LOH in broad regions on chromosome 13, including Ptch1 locus and distally-extending telomeric portion (S-type), while tumors induced after 3Gy irradiation showed losses only at interstitial markers around Ptch1 locus (R-type), and tumors induced after lower doses exhibited a clear dose-dependent increase in the ratio of R-type to S-type (Ishida et al., at this conference). To explore the difference between S-typed and R-typed tumors, we performed integrated array-CGH and expression microarray analysis on 6 S-typed and 6 R-typed tumors. Array-CGH analysis revealed that copy-number reduction around Ptch1 locus occurred only in R-typed tumors, suggesting that wild-type Ptch1 allele was lost by deletion in R-typed tumors, while it was due to mitotic recombination in S-typed tumors. In addition, all 12 tumors had copy-number gains of whole chromosome 6 in some degree. In expression analysis, more than 1,000 genes showed statistically significant difference between groups of S- and R-typed tumors. Importantly, many of them were located within the commonly deleted region around Ptch1 locus and showed decreased expression by half in R-typed tumors as if they were influenced directly by the copy-number reduction there. On the other hand, many genes on chromosome 6 showed increased expressions with showing tight correlation with levels of aneuploidy, that were calculated based on results by array-CGH analysis. These data suggest that copy-number aberrations, some of which are typically caused by irradiation, lead to considerable changes in transcriptome possibly by both cis- and trans-acting manners.
