Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Abstract

Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung).

Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type.

Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected).

Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Figure 1.

Histograms of STAT_acute and rSTAT_acute distribution per cancer type and curve of normal log distribution. STAT = standardized total average toxicity.

Figure 2.

Manhattan (left) and Q-Q (right) plots of the overall meta-analysis for STAT_acute and rSTAT_acute. Mirror. Manhattan plot: The GWAS for STAT_acute and rSTAT_acute are displayed in the top and bottom panels, respectively. The x-axis represents genomic locations, while the y-axis indicates ‒log₁₀P values for SNV associations with the outcome. Each SNV is a dot. Q-Q plot: Observed ‒log₁₀P values are on the y-axis, and expected ‒log₁₀P values are on the x-axis. Every SNV is represented as a dot, with the red line signifying the null hypothesis of no genuine association. Notable deviations from the expected P value distribution appear primarily at the tail, complemented by the λ coefficients, indicating effective control of population stratification. GWAS = genome-wide association study; Q-Q = quintile-quintile; SNV = single-nucleotide variant; STAT = standardized total average toxicity.

Figure 3.

Locus zoom plot for the top locus associated with rSTAT_acute. The purple diamond shows the top single-nucleotide variant and variants in red are in linkage disequilibrium with the top single-nucleotide variant. The y-axis shows observed −log₁₀P values, and the x-axis shows the position across the genome, with genes mapped there. STAT = standardized total average toxicity

Figure 4.

Tissue expression analysis in 53 tissue types for genes related to overall rSTAT_acute. Tissue expression analysis testing the positive relationship between all annotated genes using the full distribution of single-nucleotide variant P values and the average expression of genes per tissue type based on Genotype-Tissue Expression RNA sequencing data. DEG = differentially expressed gene set; STAT = standardized total average toxicity.