CBIO-05. UNDERSTANDING MECHANISMS OF IDH-MUTANT, 1p19q INTACT GLIOMA PROGRESSION THROUGH USE OF LATEST-GENERATION MASS SPECTROMETRY
Year: 2017
Type: conference-abstract
Abstract: Gliomas are the most common primary brain tumors in adults. Driver mutations in Isocitrate Dehydrogenase 1 and 2 (IDH1/2) result in overproduction of an oncometabolite, 2-hydroxy-keto glutartate with subsequent downstream Tp53 mutations or loss of 1p19q. IDH-mutated low grade gliomas have a relatively indolent clinical course; however over time they migrate to a higher grade. Initial standard of care involves surgery with the addition of radiation and alkylating chemotherapy for more aggressive lesions. Molecular studies of recurrent lesions have documented numerous DNA mutations consistent with alkylating agent damage in those treated with chemotherapy. To ascertain the natural history of progressive IDH mutated 1p19q intact tumors this study compared differences in the proteomic profiles of 6 matched pairs of primary and recurrent lesions from patients who had NOT received chemotherapy. Three patients presented with grade 2 lesions and following resection were observed. Time to recurrence (TTR) was 38, 30 and 14 months respectively. Three patients presented with grade 3 lesions and received radiotherapy alone following surgery. Their TTR was 99, 52 and 71 months. Protein was extracted from frozen specimens and following quality control analyzed by SWATH-MS (on a Sciex TripleToF 6600). Overall, 1781 proteins were identified by SWATH-MS analysis. Of those proteins, 40 were significantly differentially expressed (FC ≥2-fold; p ≤ 0.05) between primary and recurrent specimens. In both datasets, these key proteins were associated with activation of the Acute Phase Response, Cell Death and Survival and Cellular Compromise, Development and Movement. Proteins significantly differentially expressed included PTPRZ1, GLS, IGFBP7 and LUM, which are involved in tumor cell proliferation and migration, angiogenesis and chemotherapy resistance. The identification of differentially expressed proteins will improve our understanding of the mechanisms driving recurrence and progression of gliomas and may also reveal potential novel targets for additional therapies for this deadly cancer.
Source: Neuro-Oncology
Authors: Angela Cho, Sarah Hayes, Amanda Hudson, Emily Colvin, Helen Wheeler, Viive Howell
Institutions: The University of Sydney, Royal North Shore Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767959444