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dc.contributor.authorNaderi, E
dc.contributor.authorAguado-Barrera, ME
dc.contributor.authorSchack, LMH
dc.contributor.authorDorling, L
dc.contributor.authorRattay, T
dc.contributor.authorFachal, L
dc.contributor.authorSummersgill, H
dc.contributor.authorMartínez-Calvo, L
dc.contributor.authorWelsh, C
dc.contributor.authorDudding, T
dc.contributor.authorOdding, Y
dc.contributor.authorVarela-Pazos, A
dc.contributor.authorJena, R
dc.contributor.authorThomson, DJ
dc.contributor.authorSteenbakkers, RJHM
dc.contributor.authorDennis, J
dc.contributor.authorLobato-Busto, R
dc.contributor.authorAlsner, J
dc.contributor.authorNess, A
dc.contributor.authorNutting, C
dc.contributor.authorGómez-Caamaño, A
dc.contributor.authorEriksen, JG
dc.contributor.authorThomas, SJ
dc.contributor.authorBates, AM
dc.contributor.authorWebb, AJ
dc.contributor.authorChoudhury, A
dc.contributor.authorRosenstein, BS
dc.contributor.authorTaboada-Valladares, B
dc.contributor.authorHerskind, C
dc.contributor.authorAzria, D
dc.contributor.authorDearnaley, DP
dc.contributor.authorde Ruysscher, D
dc.contributor.authorSperk, E
dc.contributor.authorHall, E
dc.contributor.authorStobart, H
dc.contributor.authorChang-Claude, J
dc.contributor.authorDe Ruyck, K
dc.contributor.authorVeldeman, L
dc.contributor.authorAltabas, M
dc.contributor.authorDe Santis, MC
dc.contributor.authorFarcy-Jacquet, M-P
dc.contributor.authorVeldwijk, MR
dc.contributor.authorSydes, MR
dc.contributor.authorParliament, M
dc.contributor.authorUsmani, N
dc.contributor.authorBurnet, NG
dc.contributor.authorSeibold, P
dc.contributor.authorSymonds, RP
dc.contributor.authorElliott, RM
dc.contributor.authorBultijnck, R
dc.contributor.authorGutiérrez-Enríquez, S
dc.contributor.authorMollà, M
dc.contributor.authorGulliford, SL
dc.contributor.authorGreen, S
dc.contributor.authorRancati, T
dc.contributor.authorReyes, V
dc.contributor.authorCarballo, A
dc.contributor.authorPeleteiro, P
dc.contributor.authorSosa-Fajardo, P
dc.contributor.authorParker, C
dc.contributor.authorFonteyne, V
dc.contributor.authorJohnson, K
dc.contributor.authorLambrecht, M
dc.contributor.authorVanneste, B
dc.contributor.authorValdagni, R
dc.contributor.authorGiraldo, A
dc.contributor.authorRamos, M
dc.contributor.authorDiergaarde, B
dc.contributor.authorLiu, G
dc.contributor.authorLeal, SM
dc.contributor.authorChua, MLK
dc.contributor.authorPring, M
dc.contributor.authorOvergaard, J
dc.contributor.authorCascallar-Caneda, LM
dc.contributor.authorDuprez, F
dc.contributor.authorTalbot, CJ
dc.contributor.authorBarnett, GC
dc.contributor.authorDunning, AM
dc.contributor.authorVega, A
dc.contributor.authorAndreassen, CN
dc.contributor.authorLangendijk, JA
dc.contributor.authorWest, CML
dc.contributor.authorAlizadeh, BZ
dc.contributor.authorKerns, SL
dc.contributor.authorRadiogenomics Consortium,
dc.identifier.citationJNCI Cancer Spectrum, 2023, pp. pkad088 -
dc.description.abstractBACKGROUND: 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.
dc.format.extentpkad088 -
dc.publisherOxford University Press (OUP)
dc.relation.ispartofJNCI Cancer Spectrum
dc.subjectSNP-based heritability
dc.subjectacute radiation-induced toxicity
dc.titleLarge-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
pubs.organisational-groupICR/Primary Group
pubs.organisational-groupICR/Primary Group/ICR Divisions
pubs.organisational-groupICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-groupICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-groupICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-groupICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-groupICR/Primary Group/ICR Divisions/Closed research teams/Clinical Academic Radiotherapy (Dearnaley)
pubs.publication-statusPublished online
icr.researchteamClinic Acad RT Dearnaley
icr.researchteamClin Trials & Stats Unit
dc.contributor.icrauthorDearnaley, David
dc.contributor.icrauthorHall, Emma
icr.provenanceDeposited by Mrs Jessica Perry (impersonating Prof Emma Hall) on 2023-11-14. Deposit type is initial. No. of files: 1. Files: Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers..pdf
icr.provenanceDeposited by Mr Arek Surman (impersonating Prof Emma Hall) on 2023-11-15. Deposit type is subsequent. No. of files: 1. Files: pkad088.pdf

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