Journal Article

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

Vega, Ana, West, Catharine M L, Mollà, Meritxell, Valdagni, Riccardo, Dennis, Joe, Nutting, Chris, Altabas, Manuel, Bultijnck, Renée, Rattay, Tim, Gutiérrez-Enríquez, Sara, Kerns, Sarah L, Schack, Line M H, Varela-Pazos, Ana, Rosenstein, Barry S, Talbot, Christopher J, Dudding, Tom, Ness, Andy, Choudhury, Ananya, Carballo, Ana, Rancati, Tiziana, Andreassen, Christian Nicolaj, Alizadeh, Behrooz Z, Lambrecht, Maarten, De Ruyck, Kim, Summersgill, Holly, Elliott, Rebecca M, Johnson, Kerstie, Pring, Miranda, Bates, Amy M, Liu, Geoffrey, Alsner, Jan, Usmani, Nawaid, Reyes, Victoria, Gulliford, Sarah L, Veldeman, Liv, Vanneste, Ben, Parliament, Matthew, Sperk, Elena, Leal, Suzanne M, Stobart, Hilary, Ramos, Mónica, Webb, Adam J, Hall, Emma, Dorling, Leila, Seibold, Petra, Lobato-Busto, Ramón, Barnett, Gillian C, Fachal, Laura, Welsh, Ceilidh, Langendijk, Johannes A, Chang-Claude, Jenny, Green, Sheryl, Eriksen, Jesper G, Odding, Yasmin, Veldwijk, Marlon R, Steenbakkers, Roel J H M, Diergaarde, Brenda, Duprez, Fréderic, Dunning, Alison M, Jena, Rajesh, De Santis, Maria Carmen, Azria, David, Thomson, David J, Sydes, Ma

2023

Overview

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.

• Publisher: Oxford University Press
• Subject: Breast / Cancer / Genetic Predisposition to Disease / Genome-Wide Association Study / Genomes / Humans / Male / Neoplasms - genetics / Neoplasms - radiotherapy / Prostate / Radiation / Radiation therapy / Toxicity