Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.
Cancer genomics
Diffuse glioma
Homologous recombination repair
Longitudinal analysis
Microhomology-mediated end-joining
Non-homologous end-joining
RNA-sequencing
Secondary glioblastoma
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
06 11 2023
06 11 2023
Historique:
received:
06
09
2023
accepted:
17
10
2023
medline:
8
11
2023
pubmed:
7
11
2023
entrez:
7
11
2023
Statut:
epublish
Résumé
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, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas 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 (TMZ) 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. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.
Identifiants
pubmed: 37932833
doi: 10.1186/s40478-023-01669-9
pii: 10.1186/s40478-023-01669-9
pmc: PMC10629206
doi:
Substances chimiques
Temozolomide
YF1K15M17Y
Isocitrate Dehydrogenase
EC 1.1.1.41
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
176Subventions
Organisme : Academy of Finland
ID : 312043
Organisme : Academy of Finland
ID : 310829
Organisme : Academy of Finland
ID : 333545
Informations de copyright
© 2023. The Author(s).
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