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

TITLE=DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1359652

DOI=10.3389/fonc.2024.1359652

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Glioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the <italic>MGMT</italic> 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 <italic>MGMT</italic> methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors.</p></sec><sec><title>Methods</title><p>We analyzed <italic>DIAPH3</italic> 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 <italic>DIAPH3</italic> expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the <italic>DIAPH3</italic> promoter using a targeted deep bisulfite sequencing approach.</p></sec><sec><title>Results</title><p>We found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in <italic>DIAPH3</italic>, respectively. We scrutinized the expression of <italic>DIAPH3</italic> at single cell level and detected an overlap with <italic>MKI67</italic> expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed <italic>DIAPH3</italic> expression in our cohort and uncovered a positive correlation between <italic>DIAPH3</italic> mRNA level and patient’s survival. The effect of <italic>DIAPH3</italic> was prominent in <italic>MGMT</italic>-methylated glioblastoma. Finally, we report that the expression of <italic>DIAPH3</italic> is at least partially regulated by the methylation of three CpG sites in the promoter region.</p></sec><sec><title>Conclusion</title><p>We propose that combining the <italic>DIAPH3</italic> expression with <italic>MGMT</italic> methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with <italic>MGMT</italic>-methylated glioblastoma.</p></sec>