Journal Article

DKFZ-2023-02138

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers.

Naderi, E. ; Aguado-Barrera, M. E. ; Schack, L. M. H. ; Dorling, L. ; Rattay, T. ; Fachal, L. ; Summersgill, H. ; Martínez-Calvo, L. ; Welsh, C. ; Dudding, T. ; Odding, Y. ; Varela-Pazos, A. ; Jena, R. ; Thomson, D. J. ; Steenbakkers, R. J. H. M. ; Dennis, J. ; Lobato-Busto, R. ; Alsner, J. ; Ness, A. ; Nutting, C. ; Gómez-Caamaño, A. ; Eriksen, J. G. ; Thomas, S. J. ; Bates, A. M. ; Webb, A. J. ; Choudhury, A. ; Rosenstein, B. S. ; Taboada-Valladares, B. ; Herskind, C. ; Azria, D. ; Dearnaley, D. P. ; de Ruysscher, D. ; Sperk, E. ; Hall, E. ; Stobart, H. ; Chang-Claude, J.DKFZ* ; De Ruyck, K. ; Veldeman, L. ; Altabas, M. ; De Santis, M. C. ; Farcy-Jacquet, M.-P. ; Veldwijk, M. R. ; Sydes, M. R. ; Parliament, M. ; Usmani, N. ; Burnet, N. G. ; Seibold, P.DKFZ* ; Symonds, R. P. ; Elliott, R. M. ; Bultijnck, R. ; Gutiérrez-Enríquez, S. ; Mollà, M. ; Gulliford, S. L. ; Green, S. ; Rancati, T. ; Reyes, V. ; Carballo, A. ; Peleteiro, P. ; Sosa-Fajardo, P. ; Parker, C. ; Fonteyne, V. ; Johnson, K. ; Lambrecht, M. ; Vanneste, B. ; Valdagni, R. ; Giraldo, A. ; Ramos, M. ; Diergaarde, B. ; Liu, G. ; Leal, S. M. ; Chua, M. L. K. ; Pring, M. ; Overgaard, J. ; Cascallar-Caneda, L. M. ; Duprez, F. ; Talbot, C. J. ; Barnett, G. C. ; Dunning, A. M. ; Vega, A. ; Andreassen, C. N. ; Langendijk, J. A. ; West, C. M. L. ; Alizadeh, B. Z. ; Kerns, S. L. ; Consortium, O. t. b. o. t. R. (Collaboration Author)

2023
Oxford University Press Oxford

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Please use a persistent id in citations: doi:10.1093/jncics/pkad088

Abstract: 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).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.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).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.

Keyword(s): GWAS ; Radiogenomics ; SNP-based heritability ; acute radiation-induced toxicity

Note: 2023 Oct 31;7(6):pkad088

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Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2023

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; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Emerging Sources Citation Index ; Fees ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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