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

Elnaz Naderi; Miguel E Aguado-Barrera; Line M H Schack; Leila Dorling; Tim Rattay; Laura Fachal; Holly Summersgill; Laura Martínez-Calvo; Ceilidh Welsh; Tom Dudding; Yasmin Odding; Ana Varela-Pazos; Rajesh Jena; David J Thomson; Roel J H M Steenbakkers; Joe Dennis; Ramón Lobato-Busto; Jan Alsner; Andy Ness; Chris Nutting; Antonio Gómez-Caamaño; Jesper G Eriksen; Steve J Thomas; Amy M Bates; Adam J Webb; Ananya Choudhury; Barry S Rosenstein; Begona Taboada-Valladares; Carsten Herskind; David Azria; David P Dearnaley; Dirk de Ruysscher; Elena Sperk; Emma Hall; Hilary Stobart; Jenny Chang-Claude; Kim De Ruyck; Liv Veldeman; Manuel Altabas; Maria Carmen De Santis; Marie-Pierre Farcy-Jacquet; Marlon R Veldwijk; Matthew R Sydes; Matthew Parliament; Nawaid Usmani; Neil G Burnet; Petra Seibold; R Paul Symonds; Rebecca M Elliott; Renée Bultijnck; Sara Gutiérrez-Enríquez; Meritxell Mollà; Sarah L Gulliford; Sheryl Green; Tiziana Rancati; Victoria Reyes; Ana Carballo; Paula Peleteiro; Paloma Sosa-Fajardo; Chris Parker; Valérie Fonteyne; Kerstie Johnson; Maarten Lambrecht; Ben Vanneste; Riccardo Valdagni; Alexandra Giraldo; Mónica Ramos; Brenda Diergaarde; Geoffrey Liu; Suzanne M Leal; Melvin L K Chua; Miranda Pring; Jens Overgaard; Luis M Cascallar-Caneda; Fréderic Duprez; Christopher J Talbot; Gillian C Barnett; Alison M Dunning; Ana Vega; Christian Nicolaj Andreassen; Johannes A Langendijk; Catharine M L West; Behrooz Z Alizadeh; Sarah L Kerns; Radiogenomics Consortium

doi:10.1093/jncics/pkad088

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

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

Elnaz Naderi, Miguel E Aguado-Barrera, Line M H Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, Laura Martínez-Calvo, Ceilidh Welsh, Tom Dudding, …

JNCI cancer spectrum, Vol.7(6), pkad088

31/10/2023

DOI: https://doi.org/10.1093/jncics/pkad088

PMID: 37862240

Résumé

Breast

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Male

Neoplasms - genetics

Neoplasms - radiotherapy

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). 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. 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). 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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Titre: Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Créateurs - sans rôle: Elnaz Naderi - Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA
Miguel E Aguado-Barrera - Instituto de Investigación Sanitaria de Santiago
Line M H Schack - NIDO | Centre for Research and Education, Gødstrup Hospital, Herning, Denmark
Leila Dorling - University of Cambridge
Tim Rattay - University of Leicester
Laura Fachal - University of Cambridge
Holly Summersgill - Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK
Laura Martínez-Calvo - Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
Ceilidh Welsh - Department of Oncology, University of Cambridge, Cambridge, UK
Tom Dudding - MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
Yasmin Odding - Bristol Cancer Institute, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
Ana Varela-Pazos - Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
Rajesh Jena - University of Cambridge
David J Thomson - The Christie NHS Foundation Trust, Manchester, UK
Roel J H M Steenbakkers - Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands
Joe Dennis - Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
Ramón Lobato-Busto - Complexo Hospitalario Universitario A Coruña
Jan Alsner - Aarhus University Hospital
Andy Ness - Bristol Dental School, University of Bristol, Bristol, UK
Chris Nutting - Head and Neck Unit, The Royal Marsden Hospital, London, UK
Antonio Gómez-Caamaño - Complexo Hospitalario Universitario A Coruña
Jesper G Eriksen - Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
Steve J Thomas - Bristol Dental School, University of Bristol, Bristol, UK
Amy M Bates - Department of Oncology, University of Cambridge, Cambridge, UK
Adam J Webb - University of Leicester
Ananya Choudhury - University of Manchester
Barry S Rosenstein - Icahn School of Medicine at Mount Sinai
Begona Taboada-Valladares - Complexo Hospitalario Universitario A Coruña
Carsten Herskind - Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
David Azria - Institut de Recherche en Cancérologie de Montpellier
David P Dearnaley - Royal Marsden NHS Foundation Trust
Dirk de Ruysscher - Maastricht University
Elena Sperk - University of Mannheim
Emma Hall - Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK
Hilary Stobart - Patient Advocate, Independent Cancer Patients' Voice, London, UK
Jenny Chang-Claude - University Medical Center Hamburg-Eppendorf
Kim De Ruyck - Ghent University Hospital
Liv Veldeman - Ghent University Hospital
Manuel Altabas - Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Maria Carmen De Santis - Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Marie-Pierre Farcy-Jacquet - Fédération Universitaire d'Oncologie Radiothérapie d'Occitanie Méditérranée, Département d'Oncologie Radiothérapie, CHU Carémeau, Nîmes, France
Marlon R Veldwijk - Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Matthew R Sydes - MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
Matthew Parliament - University of Alberta
Nawaid Usmani - Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
Neil G Burnet - The Christie NHS Foundation Trust
Petra Seibold - Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
R Paul Symonds - Cancer Research Centre, University of Leicester, Leicester, UK
Rebecca M Elliott - University of Manchester
Renée Bultijnck - Ghent University Hospital
Sara Gutiérrez-Enríquez - Vall d'Hebron Institute of Oncology
Meritxell Mollà - Vall d'Hebron Hospital Universitari
Sarah L Gulliford - Department of Medical Physics and Biomedical Engineering, University College London, UK
Sheryl Green - Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Tiziana Rancati - Fondazione IRCCS Istituto Nazionale dei Tumori
Victoria Reyes - Vall d'Hebron Hospital Universitari
Ana Carballo - Complexo Hospitalario Universitario A Coruña
Paula Peleteiro - Complexo Hospitalario Universitario A Coruña
Paloma Sosa-Fajardo - Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
Chris Parker - Department of Medical Physics and Biomedical Engineering, University College London, UK
Valérie Fonteyne - Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium
Kerstie Johnson - University of Leicester
Maarten Lambrecht - Radiation Oncology, KU Leuven, Leuven, Belgium
Ben Vanneste - Department of Radiation Oncology (Maastro Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Riccardo Valdagni - Fondazione IRCCS Istituto Nazionale dei Tumori
Alexandra Giraldo - Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Mónica Ramos - Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Brenda Diergaarde - Department of Human Genetics, School of Public Health, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
Geoffrey Liu - Princess Margaret Cancer Centre, Temerty Faculty of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Suzanne M Leal - Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA
Melvin L K Chua - Duke-NUS Medical School, Oncology Academic Clinical Programme, Singapore
Miranda Pring - Bristol Dental School, University of Bristol, Bristol, UK
Jens Overgaard - Aarhus University Hospital
Luis M Cascallar-Caneda - Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
Fréderic Duprez - Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium
Christopher J Talbot - Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
Gillian C Barnett - University of Cambridge
Alison M Dunning - University of Cambridge
Ana Vega - Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
Christian Nicolaj Andreassen - Aarhus University Hospital
Johannes A Langendijk - Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands
Catharine M L West - Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester, UK
Behrooz Z Alizadeh - University Medical Center Groningen
Sarah L Kerns - Medical College of Wisconsin
Radiogenomics Consortium
Détails de publication: JNCI cancer spectrum, Vol.7(6), pkad088
Note de subvention: 25351 / Cancer Research UK Wellcome Trust
Identifiants: 99141177709311
Unité académique: Institut de Recherche en Cancérologie de Montpellier - IRCM
Langue: English
Type de ressource: Journal article