Integrated genomic characterization of endometrial carcinoma

Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Figure 1. SCNAs in endometrial carcinomas.

a, Tumours were hierarchically clustered into four groups based on SCNAs. The heat map shows SCNAs in each tumour (horizontal axis) plotted by chromosomal location (vertical axis). Chr., chromosome. b, Kaplan–Meier curves of progression-free survival for each copy-number cluster. PowerPoint slide

Figure 2. Mutation spectra across endometrial carcinomas.

a, Mutation frequencies (vertical axis, top panel) plotted for each tumour (horizontal axis). Nucleotide substitutions are shown in the middle panel, with a high frequency of C-to-A transversions in the samples with POLE exonuclease mutations. CN, copy number. b, Tumours were stratified into the four groups by (1) nucleotide substitution frequencies and patterns, (2) MSI status, and (3) copy-number cluster. SNV, single nucleotide variant. c, POLE-mutant tumours have significantly better progression-free survival, whereas copy-number high tumours have the poorest outcome. d, Recurrently mutated genes are different between the four subgroups. Shown are the mutation frequencies of all genes that were significantly mutated in at least one of the four subgroups (MUSiC, asterisk denotes FDR < 0.05). PowerPoint slide

Figure 3. Gene expression across integrated subtypes in endometrial carcinomas.

a, Supervised analysis of ∼1,500 genes significantly associated with integrated subtypes. b, Heat map of protein expression clusters, supervised by integrated subtypes. Samples are in columns; genes or proteins are in rows. PowerPoint slide

Figure 4. Pathway alterations in endometrial carcinomas.

a, The RTK/RAS/β-catenin pathway is altered through several mechanisms that exhibit mutually exclusive patterns. Alteration frequencies are expressed as a percentage of all cases. The right panel shows patterns of occurrence. b, The PI(3)K pathway has mutually exclusive PIK3CA and PIK3R1 alterations that frequently co-occur with PTEN alterations in the MSI and copy-number low subgroups. c, Heat map display of top 1,000 varying pathway features within PARADIGM consensus clusters. Samples were arranged in order of their consensus cluster membership. The genomic subtype for each sample is displayed below the consensus clusters. PowerPoint slide

Figure 5. Genomic relationships between endometrial serous-like, ovarian serous, and basal-like breast carcinomas.

a, SCNAs for each tumour type. b, Frequency of genomic alterations present in at least 10% of one tumour type. PowerPoint slide