{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:36:05Z","timestamp":1760146565735,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Italiana per la Ricerca sul Cancro (AIRC)","award":["IG 20314"],"award-info":[{"award-number":["IG 20314"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Medulloblastoma (MB) is a common primary brain cancer in children. The sonic hedgehog (SHH) pathway is indispensable for the normal development of the cerebellum, and MB is often caused by persistent SHH activation owing to mutations in pathway components. Patched1 (PTCH1) is the primary receptor for the SHH ligand and a negative regulator of the SHH signal transduction pathway. Mice heterozygous for the Ptch1 gene (Ptch1+\/\u2212) are predisposed to MB development. Irradiation of newborn Ptch1+\/\u2212 mice dramatically increases MB occurrence. A genetic background carrying the Ptch1 mutation significantly influences the risk of developing MB. This study aims to investigate the genetic background-related mechanisms that regulate radiation-induced cellular response and oncogenesis in the cerebellum. We employed multiple approaches, including: (a) analysis of cellular radiosensitivity in granule cell precursors (GCPs), the MB cells of origin, derived from Ptch1 mice with a genetic background that is sensitive (CD1) or resistant (C57Bl\/6) to the induction of radiogenic MB; (b) identification of genes differentially expressed in spontaneous and radiation-induced MBs from these two mouse strains; (c) bioinformatic analysis to correlate the expression of radiation-induced genes with survival in MB patients; and (d) examining the expression of these genes in ex vivo MBs induced by single or repeated radiation doses. We have identified a potential gene expression signature\u2014Trp53bp1, Bax, Cyclin D1, p21, and Nanog\u2014that influences tumor response. In ex vivo cultured spontaneous MBs, the expression levels of these genes increase after irradiation in CD1 mice, but not in mice with a C57Bl\/6 genetic background, suggesting that this signature could predict tumor response to radiation therapy and help develop strategies for targeting DNA damage repair in tumors. A detailed understanding of the mechanisms behind genetic background-related susceptibility to radiation-induced oncogenic responses is crucial for translational research.<\/jats:p>","DOI":"10.3390\/cells13221912","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T06:06:54Z","timestamp":1731996414000},"page":"1912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dissecting the Impact of Genetic Background on Oncogenic Response to Radiation Exposure in the Ptch1+\/\u2212 Mouse Model"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-699X","authenticated-orcid":false,"given":"Barbara","family":"Tanno","sequence":"first","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2522-1718","authenticated-orcid":false,"given":"Emiliano","family":"Fratini","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Leonardi","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-3704","authenticated-orcid":false,"given":"Flavia","family":"Novelli","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6536-7209","authenticated-orcid":false,"given":"Valentina","family":"Pisano","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0912-9287","authenticated-orcid":false,"given":"Mariateresa","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simonetta","family":"Pazzaglia","sequence":"additional","affiliation":[{"name":"Division of Biotechnologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Via Anguillarese 301, 00123 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/nature09587","article-title":"Subtypes of medulloblastoma have distinct developmental origins","volume":"468","author":"Gibson","year":"2010","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/nrc3410","article-title":"Medulloblastomics: The end of the beginning","volume":"12","author":"Northcott","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1242\/dev.126.14.3089","article-title":"Sonic hedgehog regulates the growth and patterning of the cerebellum","volume":"126","author":"Dahmane","year":"1999","journal-title":"Development"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0896-6273(00)80682-0","article-title":"Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog","volume":"22","author":"Scott","year":"1999","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1101\/gad.10.3.301","article-title":"Conservation of the hedgehog\/patched signaling pathway from flies to mice: Induction of a mouse patched gene by Hedgehog","volume":"10","author":"Goodrich","year":"1996","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nm0598-619","article-title":"Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome","volume":"4","author":"Hahn","year":"1998","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccr.2008.07.003","article-title":"Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells","volume":"14","author":"Yang","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.277.5329.1109","article-title":"Altered Neural Cell Fates and Medulloblastoma in Mouse patched Mutants","volume":"277","author":"Goodrich","year":"1997","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7580","DOI":"10.1038\/sj.onc.1205973","article-title":"High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice","volume":"21","author":"Pazzaglia","year":"2002","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1158\/0008-5472.CAN-03-2460","article-title":"Basal cell carcinoma and its development: Insights from radiation-induced tumors in Ptch1-deficient mice","volume":"64","author":"Mancuso","year":"2004","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1016\/j.ijrobp.2008.10.068","article-title":"Physical, heritable and age-related factors as modifiers of radiation cancer risk in patched heterozygous mice","volume":"73","author":"Pazzaglia","year":"2009","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_12","first-page":"43","article-title":"Contribution of Genetic Background to the Radiation Risk for Cancer and Non-Cancer Diseases in Ptch1+\/- Mice","volume":"197","author":"Leonardi","year":"2022","journal-title":"Radiat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1080\/09553002.2019.1665209","article-title":"Clinical and epidemiological observations on individual radiation sensitivity and susceptibility","volume":"96","author":"Seibold","year":"2020","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tanno, B., Leonardi, S., Babini, G., Giardullo, P., De Stefano, I., Pasquali, E., Saran, A., and Mancuso, M. (2017). Nanog-driven cell-reprogramming and self-renewal maintenance in Ptch1 +\/- granule cell precursors after radiation injury. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-14506-6"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111162","DOI":"10.1016\/j.celrep.2022.111162","article-title":"Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development","volume":"40","author":"Williamson","year":"2022","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Seidel, C., Heider, S., Hau, P., Glasow, A., Dietzsch, S., and Kortmann, R.D. (2021). Radiotherapy in Medulloblastoma-Evolution of Treatment, Current Concepts and Future Perspectives. Cancers, 13.","DOI":"10.3390\/cancers13235945"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1631\/jzus.B073001","article-title":"Mechanisms of inherited cancer susceptibility","volume":"1","author":"Hodgson","year":"2008","journal-title":"J. Zhejiang Univ. Sci. B."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3798","DOI":"10.1158\/0008-5472.CAN-03-3716","article-title":"Modulation of patched-associated susceptibility to radiation induced tumorigenesis by genetic background","volume":"64","author":"Pazzaglia","year":"2004","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.devcel.2014.08.010","article-title":"The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors","volume":"31","author":"Mille","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_20","first-page":"840","article-title":"Sonic hedgehog accelerates DNA replication to cause replication stress promoting cancer initiation in medulloblastoma","volume":"8","author":"Gallo","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Shao, M., Bi, T., Ding, W., Yu, C., Jiang, C., Yang, H., Sun, X., and Yang, M. (2018). OCT4 Potentiates Radio-Resistance and Migration Activity of Rectal Cancer Cells by Improving Epithelial-Mesenchymal Transition in a ZEB1 Dependent Manner. BioMed Res. Int., 2018.","DOI":"10.1155\/2018\/3424956"},{"key":"ref_22","first-page":"47","article-title":"Oct4 suppresses IR-induced premature senescence in breast cancer cells through STAT3- and NF-\u03baB-mediated IL-24 production","volume":"53","author":"Kim","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4214","DOI":"10.1038\/s41388-021-01842-1","article-title":"Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L","volume":"40","author":"Nathansen","year":"2021","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cell.2005.07.034","article-title":"Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin","volume":"123","author":"Takagi","year":"2005","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.molcel.2006.01.020","article-title":"p53 ubiquitination: Mdm2 and beyond","volume":"21","author":"Brooks","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/ncb1211","article-title":"p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression","volume":"7","author":"Lin","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5575","DOI":"10.1038\/sj.onc.1209544","article-title":"Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice","volume":"25","author":"Pazzaglia","year":"2006","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8388","DOI":"10.1073\/pnas.111006398","article-title":"Homologous DNA recombination in vertebrate cells","volume":"98","author":"Sonoda","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0960-9822(00)80005-6","article-title":"DNA double-strand break repair","volume":"9","author":"Featherstone","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1038\/onc.2011.178","article-title":"Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum","volume":"30","author":"Tanori","year":"2011","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41419-022-04644-9","article-title":"Identification of Nanog as a novel inhibitor of Rad51","volume":"13","author":"Xin","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12318","article-title":"53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark","volume":"499","author":"Canny","year":"2013","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1242\/jcs.105353","article-title":"BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair","volume":"125","author":"Chapman","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.tcb.2013.09.003","article-title":"53BP1: Pro choice in DNA repair","volume":"24","author":"Zimmermann","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Choi, W., and Lee, E.S. (2022). Therapeutic Targeting of DNA Damage Response in Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031701"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/22\/1912\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:35:09Z","timestamp":1760114109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/22\/1912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":35,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["cells13221912"],"URL":"https:\/\/doi.org\/10.3390\/cells13221912","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2024,11,19]]}}}