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

Abstract

Accurate cancer risk assessment of low-dose radiation poses many challenges that are partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. To elucidate characteristic features of radiation-induced tumors, we analyzed 163 medulloblastomas that developed either spontaneously or after X-ray irradiation at doses of 0.05-3 Gy in Ptch1 heterozygous mice. All spontaneous tumors showed loss of heterozygosity in broad regions on chromosome 13, with losses at all consecutive markers distal to Ptch1 locus (S-type). In contrast, all tumors that developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 with distal markers retained (R-type). There was a clear dose-dependent increase in the proportion of R-type tumors within the intermediate dose range, indicating that the R-type change is a reliable radiation signature. Importantly, the incidence of R-type tumors increased significantly (P = 0.007) at a dose as low as 50 mGy. Integrated array-comparative genomic hybridization and expression microarray analyses demonstrated that expression levels of many genes around the Ptch1 locus faithfully reflected the signature-associated reduction in genomic copy number. Furthermore, 573 genes on other chromosomes were also expressed differently between S-type and R-type tumors. They include genes whose expression changes during early cerebellar development such as Plagl1 and Tgfb2, suggesting a recapitulation of gene subsets functioning at distinct developmental stages. These findings provide, for the first time, solid experimental evidence for a significant increase in cancer risk by low-dose radiation at diagnostic levels and imply that radiation-induced carcinogenesis accompanies both genomic and gene expression signatures.

Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

“…The mice were hemizygous for patched (Ptch+/−), which promotes the development of SHH-MB-like tumors (Buonamici et al, 2010; Ishida et al, 2010). One study examined tumor growth in mice receiving medulloblastoma tumors (allografts) from a donor mouse lacking the murine p53 ortholog (Trp53) and a copy of patched (Buonamici et al, 2010) whereas another study examined tumors from Ptch+/−;Trp53+/+ mice (Ishida et al, 2010). All six tumors in mice receiving allografts from the Ptch+/−;Trp53−/− donor showed rearrangements consistent with chromothripsis (Data S2).…”

Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes

“…To test whether this host biology is applicable to other experimental models, we applied this gene list to published data from sporadic or radiation-preceded rat sarcomas (32) and murine Ptch1 mutant medulloblastoma (33). Most radiation-induced sarcoma and medulloblastoma were clustered by this profile (Figure S1A&B).…”

Interstitial chromosomal deletion of the tuberous sclerosis complex 2 locus is a signature for radiation‐associated renal tumors in Eker rats

“…The primer sequences and PCR conditions are listed in Table . Relative gene expression was calculated using the method . A mean value of Tsc2 expression derived from the kidneys of 6 Eker rats with Tsc2 +/+ (52 weeks of age) was used as a reference value.…”

“…Animal models are, therefore, important for investigating the contribution of a single factor to carcinogenesis. Characteristic patterns of LOH have been frequently observed in several solid tissues and tumors of mice exposed to ionizing radiation compared with nonirradiated tissues and spontaneous or chemical carcinogen‐induced tumors . Eker rats spontaneously develop malignant adenocarcinoma via premalignant proliferative lesions of the renal proximal tubular epithelium (eg, phenotypically altered tubules, atypical hyperplasia and adenoma) with 100% incidence by 1 year of age .…”