Comprehensive multiomics analysis reveals distinct differences between pediatric choroid plexus papilloma and carcinoma

Abstract

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.

Keywords: Choroid plexus tumor; Methylation sequencing; Multiomics; Whole-genome sequencing; Whole-transcriptome sequencing.

Fig. 1

An overview of sample information and genetic events from WGS data. a Summary of sample information and genetic events of 20 CPT patients. b, c Multiple sequence alignment diagrams of regions where point mutations occurred within TP53 (b) and EPHA7 (c), respectively, in several vertebrate species. A red exclamation mark indicates a perfect match across all species examined. A yellow asterisk indicates an 80% or better match across species, but not a perfect match. A green asterisk indicates more than 50% and less than 80% match across species

Fig. 2

Frequency and significance of SCNAs between CPP and CPC across the autosomal chromosomes. a Panel showing the frequency of copy number gain in each subtype. b The color bar represents the − log Q value of each arm calculated from GISTIC. c, d Same as b, a, but represents a copy number loss value

Fig. 3

Expression profile of DEGs between the subtypes of CPT. a Volcano plot showing genes that are significantly up- and downregulated between CPP and CPC. b Heatmap of DEGs between CPP and CPC. Hierarchical clustering was performed by gene (column) and sample (row) according to expression pattern. The top of the figure is colored according to the pathway to which the gene belongs. c Enrichment test of significant DEGs and their associated pathways

Fig. 4

Expression profile of DEGs between LMS (−) and LMS (+) CPC. a Volcano plot showing genes that are significantly up- and downregulated depending on LMS status in CPC. b PCR validation of DEGs that are significantly up- and downregulated between LMS (−) and LMS (+) CPC. Significant differences between groups are indicated by asterisks. *P < 0.05, **P < 0.01, ***P < 0.001 as calculated by the Wilcoxon rank-sum test

Fig. 5

Methylation profile of DMSs between CPT subtypes. a Volcano plot showing sites that are significantly hyper- and hypomethylated sites between CPP and CPC. b Heatmap of DMSs between CPP and CPC. Hierarchical clustering is performed by CpG site (column) and sample (row) according to the methylation pattern. The top of the figure indicates the genomic regions in which each site is located. c Boxplot of the degree of methylation in four types of repeat regions, grouped by CPT subtype. Significant differences between groups are indicated by asterisks.: *P < 0.05, **P < 0.01 as calculated by t test. d Copy number ratio, expression, and methylation of AK1 in different CPT subtypes. Significant differences between groups are indicated by asterisks.: *P < 0.05, **P < 0.01, ***P < 0.001 as calculated by the Wilcoxon rank-sum test

Fig. 6

Summary of genomic and epigenomic differences between CPP and CPC