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Genomic analysis of IDH-mutant astrocytoma progression to grade 4 in the treatment setting reveals changes in cell cycle, growth factor, and DNA repair pathways [ssRNA-seq]

ABSTRACT: As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing and 21 additional patients with targeted sequencing. The Cancer Genome Atlas (TCGA) data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. Tumor progression was associated with upregulation of cell cycle progression, migration, and DNA damage repair-related genes. The cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected progression-related alterations in DNA repair pathway genes associated with the promotion of error-prone DNA repair, thus facilitating tumor progression. The homologous recombination repair gene RAD51B was hemizygously deleted in all but one progressed tumor in our discovery cohort. In our retrospective analysis of patient treatment and survival timelines, the combination of postoperative radiation and chemotherapy (mainly temozolomide) outperformed radiation especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results support previous notions that treatment contributes to tumor evolution and suggest that altered DNA repair has a role in treatment resistance and tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233032 | GEO | 2023/11/15

REPOSITORIES: GEO

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Project description:As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing and 21 additional patients with targeted sequencing. The Cancer Genome Atlas (TCGA) data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. Tumor progression was associated with upregulation of cell cycle progression, migration, and DNA damage repair-related genes. The cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected progression-related alterations in DNA repair pathway genes associated with the promotion of error-prone DNA repair, thus facilitating tumor progression. The homologous recombination repair gene RAD51B was hemizygously deleted in all but one progressed tumor in our discovery cohort. In our retrospective analysis of patient treatment and survival timelines, the combination of postoperative radiation and chemotherapy (mainly temozolomide) outperformed radiation especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results support previous notions that treatment contributes to tumor evolution and suggest that altered DNA repair has a role in treatment resistance and tumor progression.

Project description:This is a model built by COPASI4.24(Build 197) This a model from the article: Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas Víctor M. Pérez-García, Luis E. Ayala-Hernández, Juan Belmonte-Beitia, Philippe Schucht, Michael Murek, Andreas Raabe, Juan Sepúlveda. PLoS Comput Biol. 2019 Jul; 15(7): e1006778. Abstract: Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the ‘in-silico twins’ of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92

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Genomic analysis of IDH-mutant astrocytoma progression to grade 4 in the treatment setting reveals changes in cell cycle, growth factor, and DNA repair pathways [ssRNA-seq]

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