Racial differences in endometrial cancer molecular portraits in The Cancer Genome Atlas

Abstract

Endometrial cancer (EC) is now the most prevalent gynaecological malignancy in the Western world. Black or African American women (BoAA) have double the mortality of Caucasian women, and their tumours tend to be of higher grade. Despite these disparities, little is known regarding the mutational landscape of EC between races. Hence, we wished to investigate the molecular features of ECs within The Cancer Genome Atlas (TCGA) dataset by racial groupings. In total 374 Caucasian, 109 BoAA and 20 Asian patients were included in the analysis. Asian women were diagnosed at younger age, 54.2 years versus 64.5 years for Caucasian and 64.9 years for BoAA women (OR 3.432; p=0.011); BoAA women were more likely to have serous type tumors (OR 2.061; p=0.008). No difference in overall survival was evident. The most frequently mutated gene in Caucasian and Asian tumours was PTEN (63% and 85%), unlike BoAA cases where it was TP53 (49%). Mutation and somatic copy number alteration (SCNA) analysis revealed an enrichment of TP53 mutations in BoAAs; whereas POLE and RPL22 mutations were more frequent in Caucasians. Major recurrent SCNA racial differences were observed at chromosomes 3p, 8, 10, and 16, which clustered BoAA tumors into 4 distinct groups and Caucasian tumors into 5 groups. There was a significantly higher frequency of somatic mutations in DNA mismatch repair genes in Asian tumours, in particular PMS2 (p=0.0036). In conclusion, inherent racial disparities appear to be present in the molecular profile of EC, which could have potential implications on clinical management.

Keywords: TCGA; endometrial cancer; ethnicity; somatic copy number aberrations.

Figure 1. Recurrent genome-wide SNCAs in each race

Genome-wide amplifications and deletions in BoAAs (A) and Caucasians (B). Recurrent SCNA in the GISTIC 2.0 SCNA data was calculated using GAIA [42] with known common CNV filtered out. Recurrent CNV were defined by FDR Q<0.15 using ten iterations. Genomic SCNA plots were generated using a custom R script, with cut-off defined also at FDR Q<0.15 for the purposes of visualisation. Large genomic differences in recurrent SCNA profiles were observed between each race.

Figure 2. Heatmap of significant SCNA groups in BoAA and Caucasians

Clustering was performed on the copy number segment mean for each recurrent SCNA region passing FDR Q<0.15. Dendrograms were generated using Euclidean distance and Ward's linkage. To identify groups of SCNA profiles in each race, we cut the dendrogram tree at different heights in order to isolate groups that fit the patterns of SCNA in the heatmap. For heatmap shading, we used a 100-element colour palette of darkblue-to-white-to-darkred and set breaks at −1 and+1.

Figure 3. Mutational profiles across endometrial cancers in BoAA and Caucasian patients

Mutation frequencies (vertical axis) are plotted for each tumor (horizontal axis) for BoAAs (A) and Caucasians (B). Details are given regarding patients demographics. Only patients with mutations are illustrated. See Supplementary Table 5 for full details of cohort numbers and groupings.

Figure 4. Survival analysis of each group

Kaplain-Meier curves by ethnicity showing 2 groups with significantly poorer outcome in Caucasians.