A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. Radiother Oncol 2014 May;111(2):178-85
Date
05/03/2014Pubmed ID
24785509DOI
10.1016/j.radonc.2014.02.012Scopus ID
2-s2.0-84902545584 (requires institutional sign-in at Scopus site) 118 CitationsAbstract
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.
Author List
Barnett GC, Thompson D, Fachal L, Kerns S, Talbot C, Elliott RM, Dorling L, Coles CE, Dearnaley DP, Rosenstein BS, Vega A, Symonds P, Yarnold J, Baynes C, Michailidou K, Dennis J, Tyrer JP, Wilkinson JS, Gómez-Caamaño A, Tanteles GA, Platte R, Mayes R, Conroy D, Maranian M, Luccarini C, Gulliford SL, Sydes MR, Hall E, Haviland J, Misra V, Titley J, Bentzen SM, Pharoah PD, Burnet NG, Dunning AM, West CMAuthor
Sarah L. Kerns PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Breast NeoplasmsDose-Response Relationship, Radiation
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Male
Polymorphism, Single Nucleotide
Prospective Studies
Prostatic Neoplasms
Radiation Injuries
Radiotherapy, Adjuvant
Radiotherapy, Intensity-Modulated