Molecular Characterization of Endometrial Carcinomas in Black and White Patients Reveals Disparate Drivers with Therapeutic Implications

Abstract

Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor-normal panel revealed a significantly higher prevalence of high-risk histologic and molecular EC subtypes in self-identified Black (n = 259) compared with White (n = 1,623) patients. Clinically actionable alterations, including high tumor mutational burden/microsatellite instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients. Ultramutated POLE molecular subtype ECs associated with favorable outcomes were rare in Black patients. Results were confirmed by genetic ancestry analysis. CCNE1 gene amplification, which is associated with aggressive clinical behavior, was more prevalent in carcinosarcomas occurring in Black than in White patients. ECs from Black and White patients display important differences in their histologic types, molecular subtypes, driver genetic alterations, and therapeutic targets.

Significance: Our comprehensive analysis of prospectively clinically sequenced ECs revealed significant differences in their histologic and molecular composition and in the presence of therapeutic targets in Black versus White patients. These findings emphasize the importance of incorporating diverse populations into molecular studies and clinical trials to address EC disparities. This article is featured in Selected Articles from This Issue, p. 2293.

Figure 1.. Histologic and molecular subtype distribution of endometrial carcinomas in self-identified Black and White patients and by genetic ancestry.

A, Distribution of histologic types of endometrial carcinomas (ECs) in Black and White patients. B, Distribution of molecular subtypes of ECs in Black and White patients, subjected to clinical MSK-IMPACT sequencing. C, Association between histologic types and molecular subtypes of ECs occurring in Black (left) and White patients (right). Note that for the purpose and presentation of this analysis, undifferentiated and unclassified ECs were combined. D, Genetic ancestry inference of self-reported Black EC patients based on MSK-IMPACT sequencing data (14), and the distribution of histologic types (left) and molecular subtypes (right). P-values, Pearson’s Chi-squared test; ns, not significant. CCC, clear cell carcinoma; CN-H/TP53abn, copy number-high/ TP53 abnormal; CN-L/NSMP, copy number-low/ no specific molecular profile; EEC, endometrioid endometrial carcinoma; MSI-H, microsatellite instability-high; NOS, not otherwise specified; Unclass, unclassified.

Figure 2.. Tumor mutational burden and chromosomal instability in endometrial carcinomas by histologic type in self-identified Black and White patients.

A, Tumor mutational burden (TMB) of endometrial carcinomas (ECs) subjected to clinical tumor-normal MSK-IMPACT sequencing in Black and White patients. TMB outliers are not graphically represented. B, Chromosomal instability as assessed by the fraction of genome altered based on clinical MSK-IMPACT sequencing of ECs in Black and White patients. C, TMB of ECs in Black and White patients by histologic type. TMB outliers are not graphically represented. D, Fraction of genome altered of ECs in Black and White patients by histologic type. G1/2, tumor grades 1 and 2; G3, tumor grade 3; Mut/Mb, number of mutations per megabase; NOS, not otherwise specified. ****, p<0.0001; ***, p<0.001, **, p<0.01, *, p<0.05; ns, not significant; Mann-Whitney U test.

Figure 3.. Somatic genetic alterations, actionable mutations and PI3K pathway-related gene alterations in endometrial carcinomas from self-identified Black and White patients.

A, Oncoprint showing pathogenic somatic mutations, amplifications and deletions affecting cancer-related genes based on clinical tumor-normal MSK-IMPACT sequencing in endometrial carcinomas (ECs) occurring in Black (left) and White patients (right). Molecular and histologic subtypes are displayed at the top. Gene names in red font are statistically significantly different between groups (q<0.1, Fisher’s Exact Test with Benjamini-Hochberg correction to control for false discovery rate). B, Frequency of activating (red) or repressing (blue) somatic genetic alterations affecting genes in the canonical PI3K signaling pathway in all ECs (top), in ECs of copy number-high/ TP53 abnormal (CN-H/TP53abn, middle left) or of copy number-low/ no specific molecular profile (CN-L/NSMP, middle right) molecular subtype, and in endometrioid grade 1/2 ECs (bottom left) and endometrioid grade 3 ECs (bottom right). The percentage of ECs in Black (left, yellow) and White (gray, right) patients harboring a somatic pathogenic mutation or gene copy number alteration is depicted under the gene name. Pathway reported in Sanchez-Vega et al (58). C, Frequency of actionable mutations/ molecular features based on OncoKB (23) in Black and White patients. Clinically actionable mutations and biomarkers from Levels 1 – 3A were compared ****, p<0.0001; ***, p<0.001, **, p<0.01, *, p<0.05; ns, not significant; Fisher’s exact test. D and E, Volcano plots showing mutation enrichment analysis of somatic genetic alterations in ECs in self-identified Black vs White patients grouped by D, molecular subtype and E, histology type. Results are represented as −Log₁₀(q) (y-axis) and Log₂(Odds Ratio) (x-axis) from two-sided Fisher’s exact tests, corrected for multiple testing by the Benjamini-Hochberg method. For genes altered in ≥5 samples, the number of alterations was compared in tumors from Black (right arrow) versus White patients (left arrow). Genes that are differentially altered after multiple corrections (q<0.1) between the corresponding groups of Black and White patients are labelled and highlighted in red. Size of the circle reflects the frequency of alteration in each displayed subgroup. Color of the gene names indicates the major type of alteration found for that given gene (somatic mutation = black; copy number amplification = blue). G1/2, tumor grades 1 and 2; G3, tumor grade 3.