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. 2022 Aug 16;13:4814. doi: 10.1038/s41467-022-32430-w

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — A To explore the genetic and clinical features associated with CD73 expression in glioblastoma, we evaluated a sub-cohort of 58 primary IDH-wildtype human glioblastoma from the BWH cohort with associated genome-wide chromosomal copy-number (array comparative genomic hybridization (ACGH)), 447-gene targeted exome sequencing (Oncopanel), MGMT promoter methylation analysis, and clinicopathologic data. These data showed a typical genomic profile for adult IDH-WT glioblastoma, with frequent polysomy 7, monosomy 10, EGFR gain/amplification, PTEN, CDKN2A, TP53 loss, and other recurrent alterations. B Correlation of CD73 and a wide variety of recurrent genomic alterations was principally notable for a significant association between EGFR gene amplification and CD73 protein expression (n = 58, p = 0.0029, t-test, unpaired, two-sided); Tukey box-and-whisker plot with midline = median, box limits = Q1 (25th percentile)/Q3 (75th percentile), whiskers = 1.5 inter-quartile range (IQR), dots = outliers (>1.5IQR)). C Analysis of bulk mRNA expression in a broader cohort of IDH-WT glioblastoma cases (TCGA, n = 145) validated these findings, showing a weakly significant (p = 0.03, r = 0.17, Pearson’s correlation test, unpaired, two-sided) direct correlation between CD73 and EGFR levels. D In the full GBM cohort (n = 194), mean CD73 protein expression level (by IHC score) was higher in primary (n = 128, mean = 2.2) vs. recurrent tumors (n = 66, mean = 1.8) (p = 0.002, t-test, unpaired, two-sided, line indicates median) and this relationship was also significant in primary IDH-WT tumors (n = 120, mean = 2.3) vs. recurrent/residual IDH-WT tumors (n = 52, mean = 1.9) (p = 0.03, t-test, unpaired, two-sided) but not primary (n = 8, mean = 1.9) vs. recurrent (n = 14, mean = 1.2) IDH-mutant GBM (p = 0.247, t-test, unpaired, two-sided). E Mantel–Cox Log-Rank survival analysis showed that elevated CD73 protein expression (by IHC) was associated with significantly (p = 0.048) shorter progression-free survival (PFS) in adult IDH-WT glioblastoma. F We next assessed a cohort of 102 pediatric tumor specimens from the Children’s Brain Tumor Network (CBTN), including most major tumor subtypes. Strong CD73 expression was present in gliomas and glioneuronal tumors, including H3K27M-mutant diffuse midline glioma, with minimal expression in medulloblastomas, ATRT, and ependymoma. G–J Across pediatric CNS tumors, CD73 expression was positively correlated with PDGFRA at the mRNA (p < 1e−15, t-test, unpaired, two-sided) and protein levels (1.79e−13; t-test, unpaired, two-sided), as well as CD39 mRNA (p < 1e−15, t-test, unpaired, two-sided) and protein (p < 1e−15; t-test, unpaired, two-sided). K Unlike adult glioblastoma, there a negative correlation with EGFR (p = 3.14e−8, t-test, unpaired, two-sided)). L Mantel–Cox Log-Rank survival analysis showed no significant difference in survival between non-H3F3A-mutated pediatric HGG with higher and lower expression of CD73 (top 50% vs. bottom 50%) (p = 0.79).