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 , Gómez-Caamaño Antonio , Eriksen Jesper G , Thomas Steve J , Bates Amy M , Webb Adam J , Choudhury Ananya , Rosenstein Barry S , Taboada-Valladares Begona , Herskind Carsten , Azria David , Dearnaley David P , de Ruysscher Dirk , Sperk Elena , Hall Emma , Stobart Hilary , Chang-Claude Jenny , De Ruyck Kim , Veldeman Liv , Altabas Manuel , De Santis Maria Carmen , Farcy-Jacquet Marie-Pierre , Veldwijk Marlon R , Sydes Matthew R , Parliament Matthew , Usmani Nawaid , Burnet Neil G , Seibold Petra , Symonds R Paul , Elliott Rebecca M , Bultijnck Renée , Gutiérrez-Enríquez Sara , Mollà Meritxell , Gulliford Sarah L , Green Sheryl , Rancati Tiziana , Reyes Victoria , Carballo Ana , Peleteiro Paula , Sosa-Fajardo Paloma , Parker Chris , Fonteyne Valérie , Johnson Kerstie , Lambrecht Maarten , Vanneste Ben , Valdagni Riccardo , Giraldo Alexandra , Ramos Mónica , Diergaarde Brenda , Liu Geoffrey , Leal Suzanne M , Chua Melvin L K , Pring Miranda , Overgaard Jens , Cascallar-Caneda Luis M , Duprez Fréderic , Talbot Christopher J , Barnett Gillian C , Dunning Alison M , Vega Ana , Andreassen Christian Nicolaj , Langendijk Johannes A , West Catharine M L , Alizadeh Behrooz Z , Kerns Sarah L ,   Radiogenomics Consortium, 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 , Gómez-Caamaño Antonio , Eriksen Jesper G , Thomas Steve J , Bates Amy M , Webb Adam J , Choudhury Ananya , Rosenstein Barry S , Taboada-Valladares Begona , Herskind Carsten , Azria David , Dearnaley David P , de Ruysscher Dirk , Sperk Elena , Hall Emma , Stobart Hilary , Chang-Claude Jenny , De Ruyck Kim , Veldeman Liv , Altabas Manuel , De Santis Maria Carmen , Farcy-Jacquet Marie-Pierre , Veldwijk Marlon R , Sydes Matthew R , Parliament Matthew , Usmani Nawaid , Burnet Neil G , Seibold Petra , Symonds R Paul , Elliott Rebecca M , Bultijnck Renée , Gutiérrez-Enríquez Sara , Mollà Meritxell , Gulliford Sarah L , Green Sheryl , Rancati Tiziana , Reyes Victoria , Carballo Ana , Peleteiro Paula , Sosa-Fajardo Paloma , Parker Chris , Fonteyne Valérie , Johnson Kerstie , Lambrecht Maarten , Vanneste Ben , Valdagni Riccardo , Giraldo Alexandra , Ramos Mónica , Diergaarde Brenda , Liu Geoffrey , Leal Suzanne M , Chua Melvin L K , Pring Miranda , Overgaard Jens , Cascallar-Caneda Luis M , Duprez Fréderic , Talbot Christopher J , Barnett Gillian C , Dunning Alison M , Vega Ana , Andreassen Christian Nicolaj , Langendijk Johannes A , West Catharine M L , Alizadeh Behrooz Z , Kerns Sarah L 
Published: October 2023

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 &lt; P &lt; 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.