Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

Autor: Rautajoki KJ; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland. kirsi.rautajoki@tuni.fi.; Tampere Institute for Advanced Study, Tampere University, Tampere, Finland. kirsi.rautajoki@tuni.fi., Jaatinen S; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Hartewig A; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Tiihonen AM; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Annala M; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Salonen I; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Valkonen M; Institute of Biomedicine, University of Turku, Turku, Finland., Simola V; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Vuorinen EM; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Kivinen A; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Rauhala MJ; Department of Neurosurgery, Tampere University Hospital and Tampere University, Tampere, Finland.; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland., Nurminen R; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland., Maass KK; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Pediatric Neuro Oncology, German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany., Lahtela SL; Department of Oncology, Tampere University Hospital and Tays Cancer Centre, Tampere, Finland., Jukkola A; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.; Department of Oncology, Tampere University Hospital and Tays Cancer Centre, Tampere, Finland., Yli-Harja O; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.; Institute for Systems Biology, Seattle, WA, USA., Helén P; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland., Pajtler KW; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Pediatric Neuro Oncology, German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany., Ruusuvuori P; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland.; Institute of Biomedicine, University of Turku, Turku, Finland., Haapasalo J; Department of Neurosurgery, Tampere University Hospital and Tampere University, Tampere, Finland.; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland., Zhang W; Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA., Haapasalo H; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland., Nykter M; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2023 Nov 06; Vol. 11 (1), pp. 176. Date of Electronic Publication: 2023 Nov 06.
DOI: 10.1186/s40478-023-01669-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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