Genomic and gene expression signatures of radiation detected in medulloblastomas after low-dose irradiation in Ptch1-heterozygous mice

Cancer risk of children following low-dose irradiation is of great concern, especially with rapid increases in diagnostic use of radiation. However, the accurate risk assessment for low-dose radiation poses many challenges. This is partly due to the inability to distinguish radiation-induced tumors from spontaneous tumors. In this study, we analyzed the dose-dependent effect of radiation on medulloblastoma development in newborn Ptch1 heterozygous mice. The incidence increased, and the latency decreased as a function of dose. Loss of heterozygosity (LOH) at Ptch1 locus in spontaneous tumors extended to telomeric regions (S-type) on chromosome 13, which was probably mediated by mitotic recombination. In contrast, tumors developed after 3 Gy irradiation exhibited interstitial deletion around Ptch1 (R-type). There was a clear dose-dependence in the proportion of R-type tumors at intermediate doses, suggesting R-type as a reliable radiation signature. R-type tumors increased significantly even at 50 mGy, strongly suggesting that low-dose radiation, indeed, contributes to tumorigenesis. Integrated array-CGH and expression microarray analyses demonstrated that expression levels of many genes on chromosome 13 faithfully reflected the signature-associated genomic copy-number reduction around Ptch1 locus. Interestingly, the signature was also connected with expression of many genes on chromosomes other than chromosome 13, including Tgfb2, Pax6 and Plagl1/Zac1, which play pivotal roles and change expression levels in the early development of cerebellar granular precursor, an origin for medulloblastoma. These findings of genome and transcriptome signatures of radiation will provide novel insights into cancer risk assessment for low-dose radiation, and the possible discriminative property of radiation carcinogenesis such as an early onset.
Keystone Symposia: Integration of Developmental Signaling Pathways