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

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 (STAT(acute)) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTAT(acute)). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV—formerly SNP)–based heritability of rSTAT(acute) in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STAT(acute) 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 rSTAT(acute) (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 rSTAT(acute) among all patients. In silico gene expression analysis showed that the genes associated with rSTAT(acute) 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.