Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.
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Date
2016-08-01Author
Kerns, SL
Dorling, L
Fachal, L
Bentzen, S
Pharoah, PDP
Barnes, DR
Gómez-Caamaño, A
Carballo, AM
Dearnaley, DP
Peleteiro, P
Gulliford, SL
Hall, E
Michailidou, K
Carracedo, Á
Sia, M
Stock, R
Stone, NN
Sydes, MR
Tyrer, JP
Ahmed, S
Parliament, M
Ostrer, H
Rosenstein, BS
Vega, A
Burnet, NG
Dunning, AM
Barnett, GC
West, CML
Radiogenomics Consortium,
Type
Journal Article
Metadata
Show full item recordAbstract
Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.
Subject
Radiogenomics Consortium
Humans
Prostatic Neoplasms
Genetic Markers
Neoplasm Staging
Treatment Outcome
Combined Modality Therapy
Radiotherapy
Odds Ratio
Cohort Studies
Genotype
Polymorphism, Single Nucleotide
Alleles
Radiation Tolerance
Quality of Life
Aged
Middle Aged
Male
Genome-Wide Association Study
Research team
ICR-CTSU Urology and Head and Neck Trials Team
Clinical Academic Radiotherapy (Dearnaley)
Radiotherapy Physics Modelling
Language
eng
Date accepted
2016-07-18
License start date
2016-08
Citation
EBioMedicine, 2016, 10 pp. 150 - 163
Publisher
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