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

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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653584/
https://www.ncbi.nlm.nih.gov/pubmed/37862240
http://dx.doi.org/10.1093/jncics/pkad088
Descripción
Sumario: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 (STAT(acute)) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTAT(acute)). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV—formerly SNP)–based heritability of rSTAT(acute) in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STAT(acute) 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 rSTAT(acute) (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 rSTAT(acute) among all patients. In silico gene expression analysis showed that the genes associated with rSTAT(acute) 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.

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