Synapse - Genomic correlates of disease progression and treatment response in prospectively characterized gliomas

Genomic correlates of disease progression and treatment response in prospectively characterized gliomas Journal Article

Authors:	Jonsson, P.; Lin, A. L.; Young, R. J.; DiStefano, N. M.; Hyman, D. M.; Li, B. T.; Berger, M. F.; Zehir, A.; Ladanyi, M.; Solit, D. B.; Arnold, A. G.; Stadler, Z. K.; Mandelker, D.; Goldberg, M. E.; Chmielecki, J.; Pourmaleki, M.; Ogilvie, S. Q.; Chavan, S. S.; McKeown, A. T.; Manne, M.; Hyde, A.; Beal, K.; Yang, T. J.; Nolan, C. P.; Pentsova, E.; Omuro, A.; Gavrilovic, I. T.; Kaley, T. J.; Diamond, E. L.; Stone, J. B.; Grommes, C.; Boire, A.; Daras, M.; Piotrowski, A. F.; Miller, A. M.; Gutin, P. H.; Chan, T. A.; Tabar, V. S.; Brennan, C. W.; Rosenblum, M.; DeAngelis, L. M.; Mellinghoff, I. K.; Taylor, B. S.
Article Title:	Genomic correlates of disease progression and treatment response in prospectively characterized gliomas
Abstract:	Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004primaryandrecurrent tumors from923glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism- specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapyassociated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAFmutant gliomas, response to agents targeting the RAF/MEK/ ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma. © 2019 American Association for Cancer Research.
Journal Title:	Clinical Cancer Research
Volume:	25
Issue:	18
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2019-09-15
Start Page:	5537
End Page:	5547
Language:	English
DOI:	10.1158/1078-0432.Ccr-19-0032
PUBMED:	31263031
PROVIDER:	scopus
PMCID:	PMC6753053
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85072233743&doi=10.1158%2f1078-0432.CCR-19-0032&partnerID=40&md5=58cc78c19f0edb6011ff28cb0d7bbf25
Notes:	Article -- Export Date: 1 October 2019 -- Source: Scopus