DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

Georges Chehade; Nady El Hajj; Mohamed Aittaleb; Maisa I Alkailani; Yosra Bejaoui; Asma Mahdi; Arwa A H Aldaalis; Michael Verbiest; Julie Lelotte; Nuria Ruiz-Reig; Irene Durá; Christian Raftopoulos; Nicolas Tajeddine; Fadel Tissir

doi:10.3389/fonc.2024.1359652

DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

Front Oncol. 2024 Feb 22:14:1359652. doi: 10.3389/fonc.2024.1359652. eCollection 2024.

Authors

Affiliations

¹ Université Catholique de Louvain, Institute of Neuroscience, Cellular and Molecular Division, Brussels, Belgium.
² College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
³ Laboratory of Population Genomics, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Department of Neuropathology, Saint-Luc University Hospital, Brussels, Belgium.
⁵ Department of Neurosurgery, Saint-Luc University Hospital, Brussels, Belgium.

Abstract

Background: Glioblastoma 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.

Methods: We 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.

Results: We 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.

Conclusion: We 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.

Keywords: MGMT methylation; O(6)-methylguanine-DNA methyltransferase; The Cancer Genome Atlas; diaphanous formin; glioblastoma; mDia2; survival.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the following grants: F/2022/1967 from the Belgian Foundation against Cancer, PDR T0236.20 from the Fund for Scientific Research (FNRS); CDR J.0175.23 from the FNRS; 0913351 from the FNRS/FWO-Excellence of Science Program; and SARA-HBKU-OVPR-TG-HBKU-INT-VPR-TG-02-10 from Hamad Bin Khalifa University. This work was made possible by NPRP-Standard (NPRP-S) 14th Cycle grant # [NPRP14S-0404-210140] from the Qatar National Research Fund (a member of Qatar Foundation). The findings herein reflect the work, and are solely the responsibility, of the authors. Open Access funding provided by the Qatar National Library. GC is a Research Fellow FNRS and the laureate of the 2021 Helaers Research Prize for Neurosurgery, and FT is an Honorary Research Director FNRS.