Association of Genetic Ancestry and Molecular Signatures with Cancer Survival Disparities: A Pan-Cancer Analysis

Abstract

While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSCC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which, seven protein-coding genes [progestin and adipoQ receptor family member 6 (PAQR6), Lck-interacting transmembrane adaptor 1 (LIME1), Sin3A-associated protein 25 (SAP25), MAX dimerization protein 3 (MXD3), coiled-coil glutamate rich protein 2 (CCER2), refilin A (RFLNA), and cathepsin W (CTSW)] significantly interacted with GA and exacerbated observed survival disparities. These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.

Significance: This large-cohort, multicancer study identifies four cancer types with cancer survival disparities and seven cancer-related genes that interact with genetic ancestry and contribute to disparities.

Graphical abstract

Figure 1.

Genome-wide GA and admixture estimates for TCGA participants. A, ADMIXTURE plot showing K = 5 GA and admixture proportions for 1000 Genomes Project continental reference populations—EUR, AF, AMR, and EAS—along with 9,818 TCGA participants. The five ancestry proportions are shown as EUR (orange), AFR (blue), NAT (red), EAS (green), and unknown (gray). B, ADMIXTURE ancestry proportions are shown for TCGA participants only, organized by SIRE groups as shown above the plot. C and D, PCA plots for TCGA participants, color-coded by SIRE (C) and GA groups (D).

Figure 2.

CSD by SIRE and GA. A, Kaplan–Meier plots of the four cancer types that show significant disparities between SIRE and/or GA groups. B, Statistical significance of SIRE and GA CSD shown as −log₁₀ of P values of pairwise log-rank tests comparing Kaplan–Meier (KM) survival curves. C, Forest plots for exponentiated hazard ratios from the Cox proportional hazard multivariable models for the four cancer types that show significant disparities between SIRE and/or GA groups. Values for categorical GA groups are shown as squares, and values for continuous GA proportions are shown as triangles. Values for SIRE groups are shown as circles. Symbols are color coded according to the SIRE or GA groups: White/EUR, orange; Black/AFR, blue; Hispanic/AMR or NAT, red; Asian/EAS, green.

Figure 3.

DEGs for cancers showing CSD between GA groups. A, Volcano plots for DEGs in four cancer types and five GA pairs showing significant CSD. The x-axes show log₂ gene expression fold-change values for reference/comparison ancestry groups, and the y-axes show the log₁₀P values for DEGs. B, Heatmap for DEGs in patients with BRCA comparing AFR versus EUR ancestry groups; each row is a single participant, and each column is a single gene. Normalized gene expression values are color-coded as shown in the legend. AFR ancestry participants are shown at the top of the heatmap (blue bar), and EUR participants are shown at the bottom (orange bar). Distributions of GA group mean expression values are shown above the heatmap.

Figure 4.

GSEA of DEGs. A, Survival and gene set enrichment are shown for AFR (blue arrows), AMR (red arrows), and EAS (green arrows) ancestry groups compared with the reference EUR group. Up arrows indicate higher survival or expression compared with the EUR reference group, and down arrows indicate lower survival or expression. B, Illustration of three cancer-related hallmark pathways (inflammatory response, EMT, and angiogenesis) and their associated functions, which are enriched for genes that are underexpressed in the AMR ancestry group for KIRC.

Figure 5.

G × GA interactions associated with CSD. DEGs with significant G × GA interactions that are associated with the relative risk of death in patients with cancer are shown. The x-axis shows the log₂ gene expression fold-change values for reference/comparison ancestry groups, and the y-axis shows the change in HRs from the Cox proportional hazard models. Genes are grouped by cancer-type/GA combinations: AFR/HNSCC, triangles; AFR/BRCA, circles; AMR/SKCM, square. The set of AFR/HNSCC genes shown in light blue show the reestimated change in HRs after differential methylation levels were added into model.