Integrative analysis of genomic and epigenetic regulation of endometrial cancer

Abstract

Endometrial carcinomas (EC) are characterized by high DNA copy numbers and DNA methylation aberrations. In this study, we sought to comprehensively explore the effect of these two factors on development and progression of EC by analyzing integrated genomic and epigenetic analysis to. We found high DNA copy number and DNA methylation abnormalities in EC, with 6308 copy-number variation genes (CNV-G) and 4376 methylation genes (MET-G). We used these CNV-G and MET-G to subcategorize the samples for prognostic analysis, and identified three molecular subtypes (iC1, iC2, iC3). Moreover, the subtypes exhibited different tumor immune microenvironment characteristics. A further analysis of their molecular characteristics revealed three potential prognostic markers (KIAA1324, nonexpresser of pathogenesis-related genes1 (NPR1) and idiopathic hypogonadotropic hypogonadism (IHH)). Notably, all three markers showed distinct CNV, DNA methylation, and gene expression profiles. Analysis of mutations among the three subtypes revealed that iC2 had fewer mutations than the other subtypes. Conversely, iC2 showed significantly higher CNV levels than other subtypes. This comprehensive analysis of genomic and epigenetic profiles identified three prognostic markers, therefore, provides new insights into the multi-layered pathology of EC. These can be utilized for accurate treatment of EC patients.

Keywords: Wnt/β-catenin; apoptosis; gemcitabine; glycolysis; proliferation.

Figure 1

Profiles of CNV-G and MET-G features. (A) z-value distribution of CNV-G and MET-G. (B) The overlap between CNV-G and MET-G. (C) Chromosome distribution (top panel) and correlation (bottom panel) of CNV-G. (D) Chromosome distribution of MET-G. (E) MET-G gene type. (F) The proportion of MET sites.

Figure 2

Molecular subtypes based on CNV-G and MET-G genes. (A) NMF-based clustering of CNV-G. (B) NMF-based clustering of MET-G. (C) KM survival curve of CNV-G subtype. (D) KM survival curve of MET-G subtype. (E) The overlap between the CNV-G subtype and the MET-G subtype. (F) The overlap between the CNV-G subtype, the MET-G subtype and the histological subtype.

Figure 3

(A) CNV levels of subtype CNV-G identified by iCluster. (B) Methylation levels of MET-G subtype identified by iCluster. (C) KM curve for the subtypes identified by iCluster. (D) KM curve for iC1 and iC2 subtypes. (E) KM curve for iC2 and iC3 subtypes. (F) KM curve for the iC1 and iC3 subtypes.

Figure 4

(A) Frequency distribution of CNV Gain and Loss. (B) Frequency distribution of CNV Gain and MetHyper. (C) Frequency distribution of CNV Gain and MetHypo. (D) Frequency distribution of CNV Loss and MetHyper. (E) Frequency distribution of CNV Loss and MetHypo. (F) Frequency distribution of MetHyper and MetHypo.

Figure 5

(A) Immune cell scores obtained from all samples. (B) A comparison of all immune cell scores among the three subtypes of iCluster. (C) A comparison of 5 immune signatures scores.

Figure 6

(A) Distribution pattern for CNV in iCluster. (B) Distribution for methylation level in iCluster. (C) Heatmap of differentially expressed genes in iCluster subtypes.

Figure 7

(A–C) A correlation of methylation of KIAA1324 gene with its expression, expression of iC subtypes, and the KM curve of the high/low expression groups. (D–F) A correlation of methylation of NPR1 gene with its expression, expression of iC subtypes, and the KM curve of the high/low expression groups. (G–I) The relationship between methylation of IHH gene with its expression, expression of iC subtypes, and the KM curve of the high/low expression group.

Figure 8

(A) Profiles of significant mutations in 48 genes across iC subtypes. (B) Distribution pattern of mutation number of the 48 genes with significant mutations. (C) Distribution of silent/nonsilent and neoantigens among iC subtypes. (D) Distribution of CNV Gain/Loss and methylated MetHyper/MetHypo among iC subtypes.