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. 2024 Apr 22;12(4):926.
doi: 10.3390/biomedicines12040926.

The Roles of AGTRAP, ALKBH3, DIVERSIN, NEDD8 and RRM1 in Glioblastoma Pathophysiology and Prognosis

Claudia Alexandra Dumitru  1 , Nikolas Walter  1 , Carl Ludwig Raven Siebert  1 , Frederik Till Alexander Schäfer  1 , Ali Rashidi  1 , Belal Neyazi  1 , Klaus-Peter Stein  1 , Christian Mawrin  2 , Ibrahim Erol Sandalcioglu  1
Affiliations

The Roles of AGTRAP, ALKBH3, DIVERSIN, NEDD8 and RRM1 in Glioblastoma Pathophysiology and Prognosis

Claudia Alexandra Dumitru et al. Biomedicines. .

Abstract

This study determined the expression of five novel biomarker candidates in IDH wild-type glioblastoma (GBM) tissues compared to non-malign brain parenchyma, as well as their prognostic relevance for the GBM patients' outcomes. The markers were analysed by immunohistochemistry in tumour tissues (n = 186) and healthy brain tissues (n = 54). The association with the patients' overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier and log-rank test. The prognostic value of the markers was determined using multivariate Cox proportional hazard models. AGTRAP, DIVERSIN, cytoplasmic NEDD8 (NEDD8c) and RRM1 were significantly overexpressed in tumour tissues compared to the healthy brain, while the opposite was observed for ALKBH3. AGTRAP, ALKBH3, NEDD8c and RRM1 were significantly associated with OS in univariate analysis. AGTRAP and RRM1 were also independent prognostic factors for OS in multivariate analysis. For PFS, only AGTRAP and NEDD8c reached significance in univariate analysis. Additionally, AGTRAP was an independent prognostic factor for PFS in multivariate models. Finally, combined analysis of the markers enhanced their prognostic accuracy. The combination AGTRAP/ALKBH3 had the strongest prognostic value for the OS of GBM patients. These findings contribute to a better understanding of the GBM pathophysiology and may help identify novel therapeutic targets in this type of cancer.

Keywords: IDH wild-type glioblastoma; biomarkers; marker combinations; overall survival; prognostic accuracy; progression-free survival.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Marker expression in GBM tissues. Representative micrographs showing weak (1 point), medium (2 points) and strong (3 points) cytoplasmic expression of (A) AGTRAP, (B) ALKBH3, (C) DIVERSIN, (D) NEDD8c and (F) RRM1. The H-score was subsequently calculated according to the formula (1 × X) + (2 × Y) + (3 × Z), where X + Y + Z = 100% of the total tumour area. (E) The 5-tier score for nuclear NEDD8 (NEDD8n) according to the percentage of positive cells.
Figure 2
Figure 2
Marker expression in healthy versus GBM tissues. Expression of (A) AGTRAP, (C) ALKBH3, (E) DIVERSIN, (G) NEDD8c and (I) RRM1 in GBM (n = 186) and tumour-free adjacent brain tissues (n = 54). The medians are shown as black lines and the percentiles (25th and 75th) as vertical boxes with error bars. The outliers are indicated by circles. Statistical analysis was performed with the Mann–Whitney U test, and the p-values are indicated in the upper-right corner of each plot. (B,D,F,H,J) Representative micrographs showing the expression of the markers in the solid tumour area (T) versus the adjacent, tumour-free tissue area (H).
Figure 3
Figure 3
Marker expression and the overall survival of GBM patients—univariate analysis. (A–F) The expression levels of the markers were dichotomised into ‘low’ and ‘high’ according to the median-split method. Kaplan–Meier curves were generated for the 36-month overall survival, and statistical analysis was performed with the log-rank test. The p-values are indicated in the upper-right corner of each plot.
Figure 4
Figure 4
New univariate analysis of DIVERSIN and RRM1 in relation to the overall survival of GBM patients. The expression levels of (A) DIVERSIN and (B) RRM1 were dichotomised into ‘low’ and ‘high’ according to the median values of the healthy tissues. Kaplan–Meier curves were generated for the 36-month overall survival, and statistical analysis was performed with the log-rank test. The p-values are indicated in the upper-right corner of each plot.
Figure 5
Figure 5
Marker expression and the progression-free survival of GBM patients—univariate analysis. (A–F) The expression levels of the markers were dichotomised into ‘low’ and ‘high’ according to the median-split method. Kaplan–Meier curves were generated for the 12-month progression-free survival and statistical analysis was performed with the log-rank test. The p-values are indicated in the upper-right corner of each plot.
Figure 6
Figure 6
Prognostic accuracy of individual and combination markers regarding OS and PFS of GBM patients. Only the markers that reached significance in the univariate survival analysis are included in this overview. Markers with stronger prognostic value are indicated by ‘>’. Markers with approximately equal prognostic value are indicated by ‘≈’.
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References

    1. Ostrom Q.T., Cioffi G., Gittleman H., Patil N., Waite K., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21:v1–v100. doi: 10.1093/neuonc/noz150. - DOI - PMC - PubMed
    1. Tan A.C., Ashley D.M., Lopez G.Y., Malinzak M., Friedman H.S., Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J. Clin. 2020;70:299–312. doi: 10.3322/caac.21613. - DOI - PubMed
    1. Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., Hawkins C., Ng H.K., Pfister S.M., Reifenberger G., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol. 2021;23:1231–1251. doi: 10.1093/neuonc/noab106. - DOI - PMC - PubMed
    1. Hegi M.E., Diserens A.C., Gorlia T., Hamou M.F., de Tribolet N., Weller M., Kros J.M., Hainfellner J.A., Mason W., Mariani L., et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 2005;352:997–1003. doi: 10.1056/NEJMoa043331. - DOI - PubMed
    1. Lopez-Ilasaca M., Liu X., Tamura K., Dzau V.J. The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling. Mol. Biol. Cell. 2003;14:5038–5050. doi: 10.1091/mbc.e03-06-0383. - DOI - PMC - PubMed

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