Fig. 2

Novel SVs, NRG3 alterations, and decreased NRG3 expression were associated with tumor progression. a The number of SVs was increased in grade 4 tumors. Clonal SVs (upper panel) were used in the subsequent analyses since they are more likely to contribute to progression. b Visualization of clonal SVs with a Circos plot. c In the ICGC cohort, the number of SVs was associated with tumor aggressiveness and recurrence. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 based on Wilcoxon rank-sum test. d Intragenic rearrangements hit NRG3 gene in two grade 4 tumors. The first exon containing the transcription start site was inverted in TG01b, and a section of the first intron was deleted in TG05b. e NRG3 RNA expression decreased in all the tumors upon progression to grade 4 (p = 0.0022, Wilcoxon rank-sum test). f Representative areas show decreased NRG3 protein expression (red) in IDHmut cells (green) in TG01b. Nuclei are stained with DAPI (blue). g NRG3 level in IDHmut cells was decreased upon progression to grade 4. Quantification of mIHC data across cells in three representative areas per sample. The mean expression for the samples was 1.67, 1.40, and 0.94 for the primary TG01, TG01a, and TG01b tumors, respectively. ****p < 0.0001 based on the Wilcoxon rank-sum test. h NRG3 expression was decreased by tumor grade, especially in grade 4 (p < 0.0001), in 595 TCGA diffuse glioma cases. *p < 0.05, ***p < 0.001, and ****p < 0.0001 based on the Wilcoxon rank-sum test. i Lower NRG3 RNA expression (below 7.7, mean in the entire TCGA diffuse glioma cohort) was associated with shorter OS in TCGA IDHmut astrocytomas (p < 0.0001, log-rank test). j In TCGA IDHmut astrocytoma data, NRG3 was recurrently hemizygously deleted, and its expression was more strongly decreased than PTEN in grade 4 IDHmut astrocytomas. Rearrangements close to genes (*) were observed in cases with gene loss