Genomic correlates of disease progression and treatment response in prospectively characterized gliomas
| Autor: | Juliann Chmielecki, Timothy A. Chan, Kathryn Beal, Philip H. Gutin, Elena Pentsova, Viviane Tabar, Michael E. Goldberg, Cameron Brennan, Malbora Manne, David B. Solit, Bob T. Li, Thomas Kaley, Adrienne Boire, Igor T. Gavrilovic, Shahiba Ogilvie, Michael F. Berger, Jacqueline B. Stone, Mariza Daras, Robert J. Young, Anna F. Piotrowski, Eli L. Diamond, David M. Hyman, Angela G. Arnold, Natalie DiStefano, Shweta S. Chavan, Antonio Omuro, Marc K. Rosenblum, Maryam Pourmaleki, Alexandra Miller, Ingo K. Mellinghoff, Zsofia K. Stadler, Philip Jonsson, Christian Grommes, Lisa M. DeAngelis, Andrew T. McKeown, Andrew L. Lin, Allison Hyde, Barry S. Taylor, Diana Mandelker, Marc Ladanyi, Ahmet Zehir, T. Jonathan Yang, Craig Nolan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research Somatic cell Kaplan-Meier Estimate medicine.disease_cause Germline 0302 clinical medicine Medicine Precision Medicine Child Promoter Regions Genetic DNA Modification Methylases Aged 80 and over Mutation Brain Neoplasms High-Throughput Nucleotide Sequencing Genomics Glioma Middle Aged Prognosis Phenotype Magnetic Resonance Imaging Treatment Outcome Oncology DNA methylation Disease Progression Female Adult Adolescent DNA repair Models Biological Article 03 medical and health sciences Young Adult Germline mutation Humans Germ-Line Mutation Aged business.industry Tumor Suppressor Proteins Genetic Variation DNA Methylation medicine.disease Image Enhancement 030104 developmental biology DNA Repair Enzymes Cancer research business 030217 neurology & neurosurgery |
| Popis: | 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 1,004 primary and recurrent tumors from 923 glioma 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 therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant 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. |
| Databáze: | OpenAIRE |
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