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Conference Paper: Integrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas
Title | Integrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas Comprehensive clinico-molecular analysis of relapsed medulloblastoma |
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Authors | |
Keywords | mutation cancer glioblastoma cytogenetics DNA methylation |
Issue Date | 2020 |
Publisher | Oxford University Press. The Journal's web site is located at https://academic.oup.com/neuro-oncology |
Citation | The 19th International Symposium on Pediatric Neuro-Oncology (ISPNO) 2020, Karuizawa, Japan, 13-16 December 2020. In Neuro-Oncology, 2020, v. 22 n. Suppl. 3, p. iii389 How to Cite? |
Abstract | INTRODUCTION: The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS: A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS: Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION: Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates. |
Description | Oral presentation - Section: Medulloblastoma (Clinical) - no. MBCL-08 |
Persistent Identifier | http://hdl.handle.net/10722/288271 |
ISSN | 2023 Impact Factor: 16.4 2023 SCImago Journal Rankings: 6.348 |
DC Field | Value | Language |
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dc.contributor.author | Kumar, R | - |
dc.contributor.author | Deng, M | - |
dc.contributor.author | Smith, KS | - |
dc.contributor.author | Liu, APY | - |
dc.contributor.author | Terhune, C | - |
dc.contributor.author | Dhall, G | - |
dc.contributor.author | Kleese4, L | - |
dc.contributor.author | Bowers, D | - |
dc.contributor.author | Chintagumpala, M | - |
dc.contributor.author | Leary, S | - |
dc.contributor.author | Nazarian, J | - |
dc.contributor.author | Orr, BA | - |
dc.contributor.author | Onar-Thomas, A | - |
dc.contributor.author | Pfister, S | - |
dc.contributor.author | Korshunov, A | - |
dc.contributor.author | Robinson, GW | - |
dc.contributor.author | Gajjar, A | - |
dc.contributor.author | Jones, D | - |
dc.contributor.author | Ramaswamy, V | - |
dc.contributor.author | Northcott, P | - |
dc.date.accessioned | 2020-10-05T12:10:25Z | - |
dc.date.available | 2020-10-05T12:10:25Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | The 19th International Symposium on Pediatric Neuro-Oncology (ISPNO) 2020, Karuizawa, Japan, 13-16 December 2020. In Neuro-Oncology, 2020, v. 22 n. Suppl. 3, p. iii389 | - |
dc.identifier.issn | 1522-8517 | - |
dc.identifier.uri | http://hdl.handle.net/10722/288271 | - |
dc.description | Oral presentation - Section: Medulloblastoma (Clinical) - no. MBCL-08 | - |
dc.description.abstract | INTRODUCTION: The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS: A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS: Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION: Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates. | - |
dc.language | eng | - |
dc.publisher | Oxford University Press. The Journal's web site is located at https://academic.oup.com/neuro-oncology | - |
dc.relation.ispartof | Neuro-Oncology | - |
dc.relation.ispartof | The 19th International Symposium on Pediatric Neuro-Oncology (ISPNO) 2020 | - |
dc.subject | mutation | - |
dc.subject | cancer | - |
dc.subject | glioblastoma | - |
dc.subject | cytogenetics | - |
dc.subject | DNA methylation | - |
dc.title | Integrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas | - |
dc.title | Comprehensive clinico-molecular analysis of relapsed medulloblastoma | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Liu, APY: apyliu@hku.hk | - |
dc.identifier.authority | Liu, APY=rp01357 | - |
dc.description.nature | abstract | - |
dc.identifier.doi | 10.1093/neuonc/noaa222.484 | - |
dc.identifier.hkuros | 314991 | - |
dc.identifier.volume | 22 | - |
dc.identifier.issue | Suppl. 3 | - |
dc.identifier.spage | iii389 | - |
dc.identifier.epage | iii389 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 1522-8517 | - |