Gillian C Barnett1, Deborah Thompson2, Laura Fachal3, Sarah Kerns4, Chris Talbot5, Rebecca M Elliott6, Leila Dorling2, Charlotte E Coles7, David P Dearnaley8, Barry S Rosenstein4, Ana Vega3, Paul Symonds9, John Yarnold8, Caroline Baynes2, Kyriaki Michailidou2, Joe Dennis2, Jonathan P Tyrer2, Jennifer S Wilkinson7, Antonio Gómez-Caamaño10, George A Tanteles11, Radka Platte2, Rebecca Mayes2, Don Conroy2, Mel Maranian2, Craig Luccarini2, Sarah L Gulliford8, Matthew R Sydes12, Emma Hall13, Joanne Haviland13, Vivek Misra14, Jennifer Titley13, Søren M Bentzen15, Paul D P Pharoah2, Neil G Burnet16, Alison M Dunning2, Catharine M L West6. 1. Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK; University of Cambridge, Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK. Electronic address: gillbarnett@doctors.org.uk. 2. Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK. 3. Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain. 4. Department of Radiation Oncology, Icahn Mount Sinai School of Medicine, NY, USA. 5. Department of Genetics, University of Leicester, UK. 6. Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK. 7. Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK. 8. Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK. 9. Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, UK. 10. Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain. 11. The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. 12. Cancer and Other Non-Infectious Diseases, MRC Clinical Trials Unit, London, UK. 13. Institute of Cancer Research-Clinical Trials and Statistics Unit, Sutton, UK. 14. Department of Clinical Oncology, Christie Hospital, Manchester, UK. 15. Division of Biostatistics and Bioinformatics, Greenebaum Cancer Center; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA. 16. University of Cambridge, Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK.
Abstract
BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.
BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.
Authors: A Sanchez; J D Schoenfeld; P L Nguyen; M Fiorentino; D Chowdhury; M J Stampfer; H D Sesso; E Giovannucci; L A Mucci; I M Shui Journal: Prostate Cancer Prostatic Dis Date: 2016-03-01 Impact factor: 5.554
Authors: Michael Baumann; Mechthild Krause; Jens Overgaard; Jürgen Debus; Søren M Bentzen; Juliane Daartz; Christian Richter; Daniel Zips; Thomas Bortfeld Journal: Nat Rev Cancer Date: 2016-03-18 Impact factor: 60.716
Authors: Deborah E Citrin; Pataje G S Prasanna; Amanda J Walker; Michael L Freeman; Iris Eke; Mary Helen Barcellos-Hoff; Molykutty J Arankalayil; Eric P Cohen; Ruth C Wilkins; Mansoor M Ahmed; Mitchell S Anscher; Benjamin Movsas; Jeffrey C Buchsbaum; Marc S Mendonca; Thomas A Wynn; C Norman Coleman Journal: Radiat Res Date: 2017-05-10 Impact factor: 2.841
Authors: Sangkyu Lee; Sarah Kerns; Harry Ostrer; Barry Rosenstein; Joseph O Deasy; Jung Hun Oh Journal: Int J Radiat Oncol Biol Phys Date: 2018-01-31 Impact factor: 7.038
Authors: Issam El Naqa; Sarah L Kerns; James Coates; Yi Luo; Corey Speers; Catharine M L West; Barry S Rosenstein; Randall K Ten Haken Journal: Phys Med Biol Date: 2017-08-01 Impact factor: 3.609
Authors: Sarah L Kerns; Suman Kundu; Jung Hun Oh; Sandeep K Singhal; Michelle Janelsins; Lois B Travis; Joseph O Deasy; A Cecile J E Janssens; Harry Ostrer; Matthew Parliament; Nawaid Usmani; Barry S Rosenstein Journal: Semin Radiat Oncol Date: 2015-05-15 Impact factor: 5.934
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Authors: Christian Nicolaj Andreassen; Barry S Rosenstein; Sarah L Kerns; Harry Ostrer; Dirk De Ruysscher; Jamie A Cesaretti; Gillian C Barnett; Alison M Dunning; Leila Dorling; Catharine M L West; Neil G Burnet; Rebecca Elliott; Charlotte Coles; Emma Hall; Laura Fachal; Ana Vega; Antonio Gómez-Caamaño; Christopher J Talbot; R Paul Symonds; Kim De Ruyck; Hubert Thierens; Piet Ost; Jenny Chang-Claude; Petra Seibold; Odilia Popanda; Marie Overgaard; David Dearnaley; Matthew R Sydes; David Azria; Christine Anne Koch; Matthew Parliament; Michael Blackshaw; Michael Sia; Maria J Fuentes-Raspall; Teresa Ramon Y Cajal; Agustin Barnadas; Danny Vesprini; Sara Gutiérrez-Enríquez; Meritxell Mollà; Orland Díez; John R Yarnold; Jens Overgaard; Søren M Bentzen; Jan Alsner Journal: Radiother Oncol Date: 2016-07-18 Impact factor: 6.280