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000285254 1001_ $$00000-0001-6549-7810$$aRautajoki, Kirsi J$$b0
000285254 245__ $$aGenomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.
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000285254 520__ $$aAs 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.
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000285254 650_7 $$2Other$$aCancer genomics
000285254 650_7 $$2Other$$aDiffuse glioma
000285254 650_7 $$2Other$$aHomologous recombination repair
000285254 650_7 $$2Other$$aLongitudinal analysis
000285254 650_7 $$2Other$$aMicrohomology-mediated end-joining
000285254 650_7 $$2Other$$aNon-homologous end-joining
000285254 650_7 $$2Other$$aRNA-sequencing
000285254 650_7 $$2Other$$aSecondary glioblastoma
000285254 7001_ $$aJaatinen, Serafiina$$b1
000285254 7001_ $$aHartewig, Anja$$b2
000285254 7001_ $$aTiihonen, Aliisa M$$b3
000285254 7001_ $$aAnnala, Matti$$b4
000285254 7001_ $$aSalonen, Iida$$b5
000285254 7001_ $$aValkonen, Masi$$b6
000285254 7001_ $$aSimola, Vili$$b7
000285254 7001_ $$aVuorinen, Elisa M$$b8
000285254 7001_ $$aKivinen, Anni$$b9
000285254 7001_ $$aRauhala, Minna J$$b10
000285254 7001_ $$aNurminen, Riikka$$b11
000285254 7001_ $$0P:(DE-He78)5100059e746b377e2e0a37c0e24f6bf7$$aMaass, Kendra K$$b12$$udkfz
000285254 7001_ $$aLahtela, Sirpa-Liisa$$b13
000285254 7001_ $$aJukkola, Arja$$b14
000285254 7001_ $$aYli-Harja, Olli$$b15
000285254 7001_ $$aHelén, Pauli$$b16
000285254 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian W$$b17$$udkfz
000285254 7001_ $$aRuusuvuori, Pekka$$b18
000285254 7001_ $$aHaapasalo, Joonas$$b19
000285254 7001_ $$aZhang, Wei$$b20
000285254 7001_ $$aHaapasalo, Hannu$$b21
000285254 7001_ $$aNykter, Matti$$b22
000285254 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-023-01669-9$$gVol. 11, no. 1, p. 176$$n1$$p176$$tActa Neuropathologica Communications$$v11$$x2051-5960$$y2023
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