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| Status |
Public on Dec 31, 2021 |
| Title |
DNA methylome evolution and reprogramming in recurrent glioblastoma |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by array
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| Summary |
Recurrent glioblastoma (GBM) has a grim prognosis, though MGMT promoter methylation and IDH mutation provide a significant survival advantage. The product of IDH mutation, 2-hydroxyglutarate, increases global DNA methylation by inhibiting demethylases. While lower-grade IDH-mutant gliomas demonstrate increased methylation as a result of this process, DNA becomes relatively hypomethylated during progression from low-grade glioma to secondary (IDH-mutant) GBM. Here we show that global DNA hypomethylation also occurs during primary (IDH-wild type) GBM recurrence. Moreover, in a phase I trial of 14 patients with recurrent (IDH-wild type) GBM, we targeted DNA hypomethylation using a methyl donor treatment. In autopsied tumors from patients treated, we observed a global increase in DNA methylation compared to initial tumor. These results suggest that hypomethylation is a marker for recurrence, and its reprogramming represents a potential therapeutic vulnerability.
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| Overall design |
glioblastoma tumors
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| Contributor(s) |
Salas LA, Stewart TG, Mobley BC, Peng C, Loganathan SN, Ma Y, Wang J, Berger MS, Absher D, Moots PL, Christensen BC, Clark SW |
| Citation(s) |
35392283 |
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Salas LA, Stewart TG, Mobley BC, Peng C, Liu J, Loganathan SN, Wang J, Ma Y, Berger MS, Absher D, Hu Y, Moots PL, Christensen BC, Clark SW. Phase I Study of High-Dose l-Methylfolate in Combination with Temozolomide and Bevacizumab in Recurrent IDH Wild-Type High-Grade Glioma. Cancer Research Communications. 2022 January; 2(1):2767-9764. NIHMSID: NIHMS1759769.doi: 10.1158/2767-9764.CRC-21-0088.
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| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 DE022772 |
MicroRNA related genetic variation and head and neck cancer |
DARTMOUTH COLLEGE |
Brock Clarke Christensen |
| R01 CA216265 |
(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes |
DARTMOUTH COLLEGE |
Brock Clarke Christensen |
| P20 GM104416 |
Early Risk Factor Related Epigenetic Alterations in Breast Cancer Pathogenesis |
DARTMOUTH COLLEGE |
Brock Clarke Christensen |
| P50 CA097257 |
SPORE: Brain Tumore SPORE Grant |
University of California San Francisco |
MITCHEL S. BERGER |
| UL1 RR024975 |
The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1 |
Vanderbilt University Medical Center |
Gordon R Bernard |
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| Submission date |
Mar 09, 2018 |
| Last update date |
Dec 20, 2022 |
| Contact name |
Lucas A. Salas |
| E-mail(s) |
lucas.a.salas@dartmouth.edu
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| Organization name |
Geisel School of Medicine at Dartmouth
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| Department |
Epidemiology
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| Lab |
Salas Lab
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| Street address |
1 Medical Center Dr, DHMC
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| City |
Lebanon |
| State/province |
NH |
| ZIP/Postal code |
03756 |
| Country |
USA |
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| Platforms (1) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA437625 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE111627_RAW.tar |
161.2 Mb |
(http)(custom) |
TAR |
| GSE111627_signal_intensities.txt.gz |
245.2 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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