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

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 Ness, Chris NuttingAntonio 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, Jens Overgaard, Christian Nicolaj Andreassen, The Radiogenomics Consortium

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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 standar- dized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic var- iants, 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 pros- tate (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 com- mon causal variants for acute radiotoxicity across cancer types.

Original languageEnglish
Article numberpkad088
JournalJNCI Cancer Spectrum
Publication statusPublished - Dec 2023


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