Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics

Chehade, Georges; Lawson, Tévi Morel; Lelotte, Julie; Daoud, Lina; Perri, Dario Di; Whenham, Nicolas; Duprez, Thierry; Tajeddine, Nicolas; Tissir, Fadel; Raftopoulos, Christian

doi:10.1007/s00701-023-05544-3

Cited by 6 publications

(8 citation statements)

References 41 publications

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“…Previously, astrocytomas were classified only as grades 1, 2, and 3, while GBM was the name given to grade 4 of this type of tumor. Today, astrocytomas can also be classified as grade 4, differentiating themselves from GBMs according to the IDH profile, with wildtype status in GBM and mutated status in astrocytomas [ 1 , 10 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…The acquisition of mutant IDH leads to a significant reprogramming of cellular metabolism, explaining the slow-growing nature of this disease and suggesting that targeting specific metabolic patterns of IDH mutants could be a valuable therapeutic approach [ 10 ]. Mutations in isocitrate IDH1 and, less commonly, IDH2 are defining features of most diffuse adult gliomas [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in isocitrate IDH1 and, less commonly, IDH2 are defining features of most diffuse adult gliomas [ 9 ]. While most IDH-mutant DGs harbor the common arginine-to-histidine mutation at codon 132 (p.R132H), approximately 10% of cases exhibit non-canonical IDH mutations, characterized by distinct radiological and histological features and a potential association with cancer predisposition genes [ 10 ]. Mandatory immunohistochemical staining for the most prevalent mutant form of IDH1 (R132H) is recommended for diagnostic purposes in all DG samples.…”

Section: Introductionmentioning

confidence: 99%

“…In cases where staining is negative, sequencing of IDH1 (codon 132) and IDH2 (codon 172) should be performed [ 8 ]. This distinction is crucial for an integrated diagnosis, particularly in patients with grade 2 and grade 3 DGs and those under 55 years of age with grade 4 tumors [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Pyrosequencing Analysis of O-6-Methylguanine-DNA Methyltransferase Methylation at Different Cut-Offs of Positivity Associated with Treatment Response and Disease-Specific Survival in Isocitrate Dehydrogenase-Wildtype Grade 4 Glioblastoma

Silva,

Di Domenico,

Caponio

et al. 2024

IJMS

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The O-6-methylguanine-DNA methyltransferase (MGMT) gene is a critical guardian of genomic integrity. MGMT methylation in diffuse gliomas serves as an important determinant of patients’ prognostic outcomes, more specifically in glioblastomas (GBMs). In GBMs, the absence of MGMT methylation, known as MGMT promoter unmethylation, often translates into a more challenging clinical scenario, tending to present resistance to chemotherapy and a worse prognosis. A pyrosequencing (PSQ) technique was used to analyze MGMT methylation status at different cut-offs (5%, 9%, and 11%) in a sample of 78 patients diagnosed with IDH-wildtype grade 4 GBM. A retrospective analysis was provided to collect clinicopathological and prognostic data. A statistical analysis was used to establish an association between methylation status and treatment response (TR) and disease-specific survival (DSS). The patients with methylated MGMT status experienced progressive disease rates of 84.6%, 80%, and 78.4% at the respective cut-offs of 5%, 9%, and 11%. The number was considerably higher when considering unmethylated patients, as all patients (100%), regardless of the cut-off, presented progressive disease. Regarding disease-specific survival (DSS), the Hazard Ratio (HR) was HR = 0.74 (0.45–1.24; p = 0.251); HR = 0.82 (0.51–1.33; p = 0.425); and HR = 0.79 (0.49–1.29; p = 0.350), respectively. Our study concludes that there is an association between MGMT unmethylation and worse TR and DSS. The 9% cut-off demonstrated a greater potential for patient survival as a function of time, which may shed light on the future need for standardization of MGMT methylation positivity parameters in PSQ.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyrosequencing Analysis of O-6-Methylguanine-DNA Methyltransferase Methylation at Different Cut-Offs of Positivity Associated with Treatment Response and Disease-Specific Survival in Isocitrate Dehydrogenase-Wildtype Grade 4 Glioblastoma

Silva,

Di Domenico,

Caponio

et al. 2024

IJMS

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“…DIAPH3 expression was analyzed in 73 samples. Clinicopathological characteristics and treatment strategies were collected from institutional medical records, as described previously ( 22 ). In brief, age was reported at the time of diagnosis, and Karnofsky performance status (KPS) was evaluated before surgery.…”

Section: Methodsmentioning

confidence: 99%

DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

Chehade,

El Hajj,

Aittaleb

et al. 2024

Front. Oncol.

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BackgroundGlioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors.MethodsWe analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach.ResultsWe found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient’s survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region.ConclusionWe propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma.

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