TY  - JOUR
AU  - Rautajoki, Kirsi J
AU  - Jaatinen, Serafiina
AU  - Hartewig, Anja
AU  - Tiihonen, Aliisa M
AU  - Annala, Matti
AU  - Salonen, Iida
AU  - Valkonen, Masi
AU  - Simola, Vili
AU  - Vuorinen, Elisa M
AU  - Kivinen, Anni
AU  - Rauhala, Minna J
AU  - Nurminen, Riikka
AU  - Maass, Kendra K
AU  - Lahtela, Sirpa-Liisa
AU  - Jukkola, Arja
AU  - Yli-Harja, Olli
AU  - Helén, Pauli
AU  - Pajtler, Kristian W
AU  - Ruusuvuori, Pekka
AU  - Haapasalo, Joonas
AU  - Zhang, Wei
AU  - Haapasalo, Hannu
AU  - Nykter, Matti
TI  - Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.
JO  - Acta Neuropathologica Communications
VL  - 11
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DKFZ-2023-02289
SP  - 176
PY  - 2023
AB  - 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.
KW  - Cancer genomics (Other)
KW  - Diffuse glioma (Other)
KW  - Homologous recombination repair (Other)
KW  - Longitudinal analysis (Other)
KW  - Microhomology-mediated end-joining (Other)
KW  - Non-homologous end-joining (Other)
KW  - RNA-sequencing (Other)
KW  - Secondary glioblastoma (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37932833
DO  - DOI:10.1186/s40478-023-01669-9
UR  - https://inrepo02.dkfz.de/record/285254
ER  -