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

Autor:	Naderi E; Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands.; Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands.; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA., Aguado-Barrera ME; Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain., Schack LMH; Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.; Department of Oncology, Gødstrup Hospital, Herning, Denmark.; NIDO | Centre for Research and Education, Gødstrup Hospital, Herning, Denmark., Dorling L; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Rattay T; Leicester Cancer Research Centre, University of Leicester, Leicester, UK., Fachal L; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Summersgill H; Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK., Martínez-Calvo L; Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain., Welsh C; Department of Oncology, University of Cambridge, Cambridge, UK., Dudding T; Bristol Dental School, University of Bristol, Bristol, UK.; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK., Odding Y; Bristol Cancer Institute, University Hospitals Bristol NHS Foundation Trust, Bristol, UK., Varela-Pazos A; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Jena R; Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK., Thomson DJ; Division of Cancer Sciences, University of Manchester, Manchester, UK.; The Christie NHS Foundation Trust, Manchester, UK., Steenbakkers RJHM; Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands., Dennis J; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Lobato-Busto R; Department of Medical Physics, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Alsner J; Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark., Ness A; Bristol Dental School, University of Bristol, Bristol, UK., Nutting C; Head and Neck Unit, The Royal Marsden Hospital, London, UK., Gómez-Caamaño A; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Eriksen JG; Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark., Thomas SJ; Bristol Dental School, University of Bristol, Bristol, UK., Bates AM; Department of Oncology, University of Cambridge, Cambridge, UK., Webb AJ; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Choudhury A; Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK., Rosenstein BS; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Taboada-Valladares B; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Herskind C; Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Azria D; Fédération Universitaire d'Oncologie Radiothérapie d'Occitanie Méditérranée, Département d'Oncologie Radiothérapie, ICM Montpellier, INSERM U1194 IRCM, University of Montpellier, Montpellier, France., Dearnaley DP; Division of Radiotherapy and Imaging, The Institute of Cancer Research Department, The Royal Marsden NHS Foundation Trust, London, UK., de Ruysscher D; MAASTRO Clinic, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands., Sperk E; Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Hall E; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK., Stobart H; Patient Advocate, Independent Cancer Patients' Voice, London, UK., Chang-Claude J; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., De Ruyck K; Departments of Basic Medical Sciences and Radiotherapy, Ghent University Hospital, Ghent, Belgium., Veldeman L; Department of Human Structure and Repair, Ghent University, Ghent, Belgium.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium., Altabas M; Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., De Santis MC; Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Farcy-Jacquet MP; Fédération Universitaire d'Oncologie Radiothérapie d'Occitanie Méditérranée, Département d'Oncologie Radiothérapie, CHU Carémeau, Nîmes, France., Veldwijk MR; Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Sydes MR; MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK., Parliament M; Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada., Usmani N; Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada., Burnet NG; The Christie NHS Foundation Trust, Manchester, UK., Seibold P; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany., Symonds RP; Cancer Research Centre, University of Leicester, Leicester, UK., Elliott RM; Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK., Bultijnck R; Department of Human Structure and Repair, Ghent University, Ghent, Belgium.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium., Gutiérrez-Enríquez S; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain., Mollà M; Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Gulliford SL; Department of Medical Physics and Biomedical Engineering, University College London, UK., Green S; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Rancati T; Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Reyes V; Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Carballo A; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Peleteiro P; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Sosa-Fajardo P; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Parker C; Department of Medical Physics and Biomedical Engineering, University College London, UK., Fonteyne V; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium., Johnson K; Leicester Cancer Research Centre, University of Leicester, Leicester, UK., Lambrecht M; Radiation Oncology, KU Leuven, Leuven, Belgium., Vanneste B; Department of Human Structure and Repair, Ghent University, Ghent, Belgium.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium.; Department of Radiation Oncology (Maastro Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands., Valdagni R; Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Giraldo A; Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Ramos M; Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Diergaarde B; Department of Human Genetics, School of Public Health, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA., Liu G; Princess Margaret Cancer Centre, Temerty Faculty of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada., Leal SM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA.; Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA., Chua MLK; Division of Radiation Oncology, National Cancer Centre Singapore, Singapore.; Duke-NUS Medical School, Oncology Academic Clinical Programme, Singapore., Pring M; Bristol Dental School, University of Bristol, Bristol, UK., Overgaard J; Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark., Cascallar-Caneda LM; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain., Duprez F; Department of Human Structure and Repair, Ghent University, Ghent, Belgium.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium., Talbot CJ; Department of Genetics and Genome Biology, University of Leicester, Leicester, UK., Barnett GC; Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK., Dunning AM; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Vega A; Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.; Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain., Andreassen CN; Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark., Langendijk JA; Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands., West CML; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester, UK., Alizadeh BZ; Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands., Kerns SL; Department of Radiation Oncology, The Medical College of Wisconsin, Milwaukee, WI, USA.
Jazyk:	angličtina
Zdroj:	JNCI cancer spectrum [JNCI Cancer Spectr] 2023 Oct 31; Vol. 7 (6).
DOI:	10.1093/jncics/pkad088
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press.)
Databáze:	MEDLINE
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