Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

On the behalf of the Radiogenomics Consortium, Elnaz Naderi, Miguel E Aguado-Barrera, Line M H Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, Laura Martínez-Calvo, Ceilidh Welsh, Tom Dudding, Yasmin Odding, Ana Varela-Pazos, Rajesh Jena, David J Thomson, Roel J H M Steenbakkers, Joe Dennis, Ramón Lobato-Busto, Jan Alsner, Andy NessChris Nutting, Antonio Gómez-Caamaño, Jesper G Eriksen, Steve J Thomas, Amy M Bates, Adam J Webb, Ananya Choudhury, Barry S Rosenstein, Begona Taboada-Valladares, Carsten Herskind, David Azria, David P Dearnaley, Dirk de Ruysscher, Elena Sperk, Emma Hall, Hilary Stobart, Jenny Chang-Claude, Kim De Ruyck, Liv Veldeman, Manuel Altabas, Maria Carmen De Santis, Marie-Pierre Farcy-Jacquet, Marlon R Veldwijk, Matthew R Sydes, Matthew Parliament, Nawaid Usmani, Neil G Burnet, Petra Seibold, R Paul Symonds, Johannes A Langendijk, Behrooz Z Alizadeh

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

METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.

RESULTS: Shared SNP-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 SNPs with rSTATacute (5.0x10-8<P-value<1.0x10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P-value=1.7x10-7), 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 x10-6, Pcorrected =0.079) as the top gene set associated with rSTATacute among all patients. In-silico gene expression analysis showed the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed Pcorrected=0.004; sun exposed Pcorrected=0.026).

CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Originele taal-2English
Artikelnummerpkad088
Aantal pagina's11
TijdschriftJNCI cancer spectrum
Volume7
Nummer van het tijdschrift6
Vroegere onlinedatum20-okt.-2023
DOI's
StatusPublished - dec.-2023

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