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Patients with a High Polygenic Risk of Breast Cancer do not have An Increased Risk of Radiotherapy Toxicity.

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Dorling, Leila 
Barnett, Gillian C 
Michailidou, Kyriaki 
Coles, Charlotte E 
Burnet, Neil G 


PURPOSE: It has been hypothesized that increased predisposition to breast cancer may correlate with radiosensitivity, and thus increased risk of toxicity following breast irradiation. This study investigated the relationship between common breast cancer risk variants and radiotherapy toxicity. EXPERIMENTAL DESIGN: SNP genotypes were determined in female breast cancer patients from the RAPPER (Radiogenomics: Assessment of polymorphisms for predicting the effects of radiotherapy) study using the Illumina CytoSNP12 genome-wide array. A further 15,582,449 genotypes were imputed using the 1000 Genomes Project reference panel. Patient (n = 1,160) polygenic risk scores were generated by summing risk-allele dosages, both unweighted and weighted by published effect sizes for breast cancer risk. Regression models were used to test associations of individual variants and polygenic risk scores with acute and late toxicity phenotypes (telangiectasia, breast edema, photographically assessed shrinkage, induration, pigmentation, breast pain, breast sensitivity, and overall toxicity). RESULTS: Genotypes of 90 confirmed breast cancer risk variants were accurately determined and polygenic risk scores were approximately normally distributed. Variant rs6964587 was associated with increased breast edema 5 years following radiotherapy (Beta, 0.22; 95% confidence interval, 0.09-0.34; P = 7 × 10(-4)). No other associations were found between individual variants or the unweighted (P > 0.17) or weighted (P > 0.13) polygenic risk score and radiotherapy toxicity. This study had >87% power to detect an association between the polygenic risk score (relative risk > 1.1) and toxicity. CONCLUSIONS: Cancer patients with a high polygenic predisposition to breast cancer do not have an increased risk of radiotherapy toxicity up to 5 years following radiotherapy but individual variants may increase risk.



Alleles, Breast Neoplasms, Cohort Studies, Combined Modality Therapy, Female, Genetic Predisposition to Disease, Genotype, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Radiation Tolerance, Risk, Tumor Burden

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Clin Cancer Res

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American Association for Cancer Research (AACR)
MRC (MR/K50127X/1)
Cancer Research UK (via University of Manchester) (A18504)
NP is Cancer Research UK Clinician Scientist Fellow. The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175), Cancer Research UK (C490/A10124), the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The ProtecT study is supported by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, HTA 96/20/99; ISRCTN20141297. The Comparative Arm of ProtecT (CAP) trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326, and C18281/A15064). UKGPCS is funded by Cancer Research UK and the NCRN. The Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust receive funding support from NIHR. SEARCH is funded by Cancer Research UK.