Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy
Abstract Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-022-00930-3 |
| _version_ | 1818000285658775552 |
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| author | Maria-Magdalena Georgescu Stephen G. Whipple Christina M. Notarianni |
| author_facet | Maria-Magdalena Georgescu Stephen G. Whipple Christina M. Notarianni |
| author_sort | Maria-Magdalena Georgescu |
| collection | DOAJ |
| description | Abstract Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFβ and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors. Video Abstract |
| first_indexed | 2024-04-14T03:19:56Z |
| format | Article |
| id | doaj.art-409e3a4c4d534740b1d87ae117ee6b47 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-04-14T03:19:56Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-409e3a4c4d534740b1d87ae117ee6b472022-12-22T02:15:21ZengBMCCell Communication and Signaling1478-811X2022-08-0120111510.1186/s12964-022-00930-3Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapyMaria-Magdalena Georgescu0Stephen G. Whipple1Christina M. Notarianni2NeuroMarkers PLLCDepartment of Neurosurgery, Louisiana State University ShreveportDepartment of Neurosurgery, Louisiana State University ShreveportAbstract Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFβ and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors. Video Abstracthttps://doi.org/10.1186/s12964-022-00930-3MedulloblastomaLi-Fraumeni syndromeFamilial adenomatous polyposisAtypical pituitary adenoma prolactinomaDesmoid fibromatosisRadiotherapy secondary malignancies |
| spellingShingle | Maria-Magdalena Georgescu Stephen G. Whipple Christina M. Notarianni Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy Cell Communication and Signaling Medulloblastoma Li-Fraumeni syndrome Familial adenomatous polyposis Atypical pituitary adenoma prolactinoma Desmoid fibromatosis Radiotherapy secondary malignancies |
| title | Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy |
| title_full | Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy |
| title_fullStr | Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy |
| title_full_unstemmed | Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy |
| title_short | Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy |
| title_sort | novel neoplasms associated with syndromic pediatric medulloblastoma integrated pathway delineation for personalized therapy |
| topic | Medulloblastoma Li-Fraumeni syndrome Familial adenomatous polyposis Atypical pituitary adenoma prolactinoma Desmoid fibromatosis Radiotherapy secondary malignancies |
| url | https://doi.org/10.1186/s12964-022-00930-3 |
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