A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.
OBJECTIVE
This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy.


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.
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.
Gillian C
GC
Barnett
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Deborah
D
Thompson
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
Laura
L
Fachal
Department of Radiation Oncology, Icahn Mount Sinai School of Medicine, NY, USA.
Sarah
S
Kerns
Department of Genetics, University of Leicester, UK.
Chris
C
Talbot
Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK.
Rebecca M
RM
Elliott
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Leila
L
Dorling
Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK.
Charlotte E
CE
Coles
Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK.
David P
DP
Dearnaley
Department of Radiation Oncology, Icahn Mount Sinai School of Medicine, NY, USA.
Barry S
BS
Rosenstein
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
Ana
A
Vega
Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, UK.
Paul
P
Symonds
Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK.
John
J
Yarnold
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Caroline
C
Baynes
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Kyriaki
K
Michailidou
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Joe
J
Dennis
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Jonathan P
JP
Tyrer
Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK.
Jennifer S
JS
Wilkinson
Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
Antonio
A
Gómez-Caamaño
The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
George A
GA
Tanteles
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Radka
R
Platte
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Rebecca
R
Mayes
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Don
D
Conroy
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Mel
M
Maranian
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Craig
C
Luccarini
Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK.
Sarah L
SL
Gulliford
Cancer and Other Non-Infectious Diseases, MRC Clinical Trials Unit, London, UK.
Matthew R
MR
Sydes
Institute of Cancer Research-Clinical Trials and Statistics Unit, Sutton, UK.
Emma
E
Hall
Institute of Cancer Research-Clinical Trials and Statistics Unit, Sutton, UK.
Joanne
J
Haviland
Department of Clinical Oncology, Christie Hospital, Manchester, UK.
Vivek
V
Misra
Institute of Cancer Research-Clinical Trials and Statistics Unit, Sutton, UK.
Jennifer
J
Titley
Division of Biostatistics and Bioinformatics, Greenebaum Cancer Center; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA.
Søren M
SM
Bentzen
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Paul D P
PD
Pharoah
University of Cambridge, Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, UK.
Neil G
NG
Burnet
Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, UK.
Alison M
AM
Dunning
Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK.
Catharine M L
CM
West
D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000235:genetics*; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects*
Adverse effects; Genetics; Genome-wide association scan; Late toxicity; Radiotherapy