Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types-Reference-Cited by-同舟云学术

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

Published:2023-10-20 Issue:6 Volume:7 Page:
ISSN:2515-5091
Container-title:JNCI Cancer Spectrum
language:en
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Author:

Naderi Elnaz¹²³^ORCID,Aguado-Barrera Miguel E⁴⁵,Schack Line M H⁶⁷⁸,Dorling Leila⁹,Rattay Tim¹⁰,Fachal Laura¹¹¹²,Summersgill Holly¹³,Martínez-Calvo Laura⁴⁵,Welsh Ceilidh¹⁴,Dudding Tom¹⁵¹⁶,Odding Yasmin¹⁷,Varela-Pazos Ana¹⁸,Jena Rajesh¹⁹,Thomson David J²⁰²¹,Steenbakkers Roel J H M²,Dennis Joe¹²^ORCID,Lobato-Busto Ramón²²,Alsner Jan⁶,Ness Andy¹⁵,Nutting Chris²³,Gómez-Caamaño Antonio⁵¹⁸,Eriksen Jesper G⁶,Thomas Steve J¹⁵,Bates Amy M¹⁴,Webb Adam J²⁴,Choudhury Ananya²⁵,Rosenstein Barry S²⁶,Taboada-Valladares Begona⁵¹⁸,Herskind Carsten²⁷,Azria David²⁸,Dearnaley David P²⁹^ORCID,de Ruysscher Dirk³⁰,Sperk Elena²⁷,Hall Emma³¹,Stobart Hilary³²,Chang-Claude Jenny³³³⁴,De Ruyck Kim³⁵,Veldeman Liv³⁶³⁷,Altabas Manuel³⁸,De Santis Maria Carmen³⁹,Farcy-Jacquet Marie-Pierre⁴⁰,Veldwijk Marlon R²⁷,Sydes Matthew R⁴¹,Parliament Matthew⁴²,Usmani Nawaid⁴²,Burnet Neil G²¹,Seibold Petra³³,Symonds R Paul⁴³,Elliott Rebecca M²⁵,Bultijnck Renée³⁶³⁷,Gutiérrez-Enríquez Sara⁴⁴,Mollà Meritxell³⁸,Gulliford Sarah L⁴⁵,Green Sheryl²⁶,Rancati Tiziana⁴⁶,Reyes Victoria³⁸,Carballo Ana⁵¹⁸,Peleteiro Paula⁵¹⁸,Sosa-Fajardo Paloma⁵¹⁸,Parker Chris⁴⁵^ORCID,Fonteyne Valérie³⁷,Johnson Kerstie¹⁰,Lambrecht Maarten⁴⁷^ORCID,Vanneste Ben³⁶³⁷⁴⁸,Valdagni Riccardo³⁹⁴⁹^ORCID,Giraldo Alexandra³⁸,Ramos Mónica³⁸,Diergaarde Brenda⁵⁰,Liu Geoffrey⁵¹^ORCID,Leal Suzanne M³⁵²,Chua Melvin L K⁵³⁵⁴,Pring Miranda¹⁵,Overgaard Jens⁶^ORCID,Cascallar-Caneda Luis M¹⁸,Duprez Fréderic³⁶³⁷,Talbot Christopher J²⁴,Barnett Gillian C¹⁹^ORCID,Dunning Alison M¹²,Vega Ana⁴⁵⁵⁵^ORCID,Andreassen Christian Nicolaj⁶⁵⁶,Langendijk Johannes A²,West Catharine M L⁵⁷,Alizadeh Behrooz Z¹,Kerns Sarah L⁵⁸^ORCID,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,

Affiliation:

1. Department of Epidemiology, University Medical Center Groningen , Groningen, The Netherlands

2. Department of Radiation Oncology, University Medical Center Groningen , Groningen, The Netherlands

3. Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center , New York, NY, USA

4. Fundación Pública Galega Medicina Xenómica , Santiago de Compostela, Spain

5. Instituto de Investigación Sanitaria de Santiago de Compostela , Santiago de Compostela, Spain

6. Department of Experimental Clinical Oncology, Aarhus University Hospital , Aarhus, Denmark

7. Department of Oncology, Gødstrup Hospital, Herning , Denmark

8. NIDO | Centre for Research and Education, Gødstrup Hospital, Herning , Denmark

9. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , Cambridge, UK

10. Leicester Cancer Research Centre, University of Leicester , Leicester, UK

11. Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, UK

12. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge , Cambridge, UK

13. Manchester Academic Health Science Centre, The Christie NHS Foundation Trust , Manchester, UK

14. Department of Oncology, University of Cambridge , Cambridge, UK

15. Bristol Dental School, University of Bristol , Bristol, UK

16. MRC Integrative Epidemiology Unit, University of Bristol , Bristol, UK

17. Bristol Cancer Institute, University Hospitals Bristol NHS Foundation Trust , Bristol, UK

18. Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS , Santiago de Compostela, Spain

19. Department of Oncology, Addenbrooke’s Hospital, University of Cambridge , Cambridge, UK

20. Division of Cancer Sciences, University of Manchester , Manchester, UK

21. The Christie NHS Foundation Trust , Manchester, UK

22. Department of Medical Physics, Complexo Hospitalario Universitario de Santiago, SERGAS , Santiago de Compostela, Spain

23. Head and Neck Unit, The Royal Marsden Hospital , London, UK

24. Department of Genetics and Genome Biology, University of Leicester , Leicester, UK

25. Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital , Manchester, UK

26. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai , New York, NY, USA

27. Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University , Mannheim, Germany

28. Fédération Universitaire d’Oncologie Radiothérapie d’Occitanie Méditérranée, Département d’Oncologie Radiothérapie, ICM Montpellier, INSERM U1194 IRCM, University of Montpellier , Montpellier, France

29. Division of Radiotherapy and Imaging, The Institute of Cancer Research Department, The Royal Marsden NHS Foundation Trust , London, UK

30. MAASTRO Clinic, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center , Maastricht, Netherlands

31. Clinical Trials and Statistics Unit, The Institute of Cancer Research , London, UK

32. Patient Advocate, Independent Cancer Patients’ Voice, London , UK

33. Division of Cancer Epidemiology, German Cancer Research Center , Heidelberg, Germany

34. University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf , Hamburg, Germany

35. Departments of Basic Medical Sciences and Radiotherapy, Ghent University Hospital , Ghent, Belgium

36. Department of Human Structure and Repair, Ghent University , Ghent, Belgium

37. Department of Radiation Oncology, Ghent University Hospital , Ghent, Belgium

38. Radiation Oncology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus , Barcelona, Spain

39. Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan, Italy

40. Fédération Universitaire d’Oncologie Radiothérapie d’Occitanie Méditérranée, Département d’Oncologie Radiothérapie, CHU Carémeau , Nîmes, France

41. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London , London, UK

42. Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta , Edmonton, AB, Canada

43. Cancer Research Centre, University of Leicester , Leicester, UK

44. Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology, Vall d’Hebron Hospital Campus , Barcelona, Spain

45. Department of Medical Physics and Biomedical Engineering, University College London , UK

46. Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan, Italy

47. Radiation Oncology, KU Leuven , Leuven, Belgium

48. Department of Radiation Oncology (Maastro Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center , Maastricht, The Netherlands

49. Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan, Italy

50. Department of Human Genetics, School of Public Health, University of Pittsburgh, UPMC Hillman Cancer Center , Pittsburgh, PA, USA

51. Princess Margaret Cancer Centre, Temerty Faculty of Medicine, Dalla Lana School of Public Health, University of Toronto , Toronto, ON, Canada

52. Taub Institute for Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center , New York, NY, USA

53. Division of Radiation Oncology, National Cancer Centre Singapore , Singapore

54. Duke-NUS Medical School, Oncology Academic Clinical Programme , Singapore

55. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela , Santiago de Compostela, Spain

56. Department of Oncology, Aarhus University Hospital , Aarhus, Denmark

57. Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital , Manchester, UK

58. Department of Radiation Oncology, The Medical College of Wisconsin , Milwaukee, WI, USA

Abstract

Abstract 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.

Funder

National Institute for Health Research

The Taylor Family Foundation

Cancer Research UK

National Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Link

https://academic.oup.com/jncics/advance-article-pdf/doi/10.1093/jncics/pkad088/52306245/pkad088.pdf

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