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- Title
Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.
- Authors
Naderi, Elnaz; Aguado-Barrera, Miguel E; Schack, Line M H; Dorling, Leila; Rattay, Tim; Fachal, Laura; Summersgill, Holly; Martínez-Calvo, Laura; Welsh, Ceilidh; Dudding, Tom; Odding, Yasmin; Varela-Pazos, Ana; Jena, Rajesh; Thomson, David J; Steenbakkers, Roel J H M; Dennis, Joe; Lobato-Busto, Ramón; Alsner, Jan; Ness, Andy; Nutting, Chris
- 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.
- Subjects
CANCER genetics; GENE expression; RNA splicing
- Publication
JNCI Cancer Spectrum, 2023, Vol 7, Issue 6, p1
- ISSN
2515-5091
- Publication type
Article
- DOI
10.1093/jncics/pkad088