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Conference Paper: Integrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas

TitleIntegrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas
Comprehensive clinico-molecular analysis of relapsed medulloblastoma
Authors
Keywordsmutation
cancer
glioblastoma
cytogenetics
DNA methylation
Issue Date2020
PublisherOxford 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?
AbstractINTRODUCTION: 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.
DescriptionOral presentation - Section: Medulloblastoma (Clinical) - no. MBCL-08
Persistent Identifierhttp://hdl.handle.net/10722/288271
ISSN
2019 Impact Factor: 10.247
2015 SCImago Journal Rankings: 3.196

 

DC FieldValueLanguage
dc.contributor.authorKumar, R-
dc.contributor.authorDeng, M-
dc.contributor.authorSmith, KS-
dc.contributor.authorLiu, APY-
dc.contributor.authorTerhune, C-
dc.contributor.authorDhall, G-
dc.contributor.authorKleese4, L-
dc.contributor.authorBowers, D-
dc.contributor.authorChintagumpala, M-
dc.contributor.authorLeary, S-
dc.contributor.authorNazarian, J-
dc.contributor.authorOrr, BA-
dc.contributor.authorOnar-Thomas, A-
dc.contributor.authorPfister, S-
dc.contributor.authorKorshunov, A-
dc.contributor.authorRobinson, GW-
dc.contributor.authorGajjar, A-
dc.contributor.authorJones, D-
dc.contributor.authorRamaswamy, V-
dc.contributor.authorNorthcott, P-
dc.date.accessioned2020-10-05T12:10:25Z-
dc.date.available2020-10-05T12:10:25Z-
dc.date.issued2020-
dc.identifier.citationThe 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.issn1522-8517-
dc.identifier.urihttp://hdl.handle.net/10722/288271-
dc.descriptionOral presentation - Section: Medulloblastoma (Clinical) - no. MBCL-08-
dc.description.abstractINTRODUCTION: 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.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at https://academic.oup.com/neuro-oncology-
dc.relation.ispartofNeuro-Oncology-
dc.relation.ispartofThe 19th International Symposium on Pediatric Neuro-Oncology (ISPNO) 2020-
dc.subjectmutation-
dc.subjectcancer-
dc.subjectglioblastoma-
dc.subjectcytogenetics-
dc.subjectDNA methylation-
dc.titleIntegrative molecular analysis of patient-matched diagnostic and relapsed medulloblastomas-
dc.titleComprehensive clinico-molecular analysis of relapsed medulloblastoma-
dc.typeConference_Paper-
dc.identifier.emailLiu, APY: apyliu@hku.hk-
dc.identifier.authorityLiu, APY=rp01357-
dc.description.natureabstract-
dc.identifier.doi10.1093/neuonc/noaa222.484-
dc.identifier.hkuros314991-
dc.identifier.volume22-
dc.identifier.issueSuppl. 3-
dc.identifier.spageiii389-
dc.identifier.epageiii389-
dc.publisher.placeUnited States-
dc.identifier.issnl1522-8517-

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