title: Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.
abstract: 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.
authors: Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Sarah L
authors: SL
authors: Kerns
authors: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Leila
authors: L
authors: Dorling
authors: Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK; Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.
authors: Laura
authors: L
authors: Fachal
authors: Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, Baltimore, USA; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA.
authors: Søren
authors: S
authors: Bentzen
authors: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Paul D P
authors: PD
authors: Pharoah
authors: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Daniel R
authors: DR
authors: Barnes
authors: Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors: Antonio
authors: A
authors: Gómez-Caamaño
authors: Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors: Ana M
authors: AM
authors: Carballo
authors: Joint Department of Physics, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5NG, UK.
authors: David P
authors: DP
authors: Dearnaley
authors: Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.
authors: Paula
authors: P
authors: Peleteiro
authors: Joint Department of Physics, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5NG, UK.
authors: Sarah L
authors: SL
authors: Gulliford
authors: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Emma
authors: E
authors: Hall
authors: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Kyriaki
authors: K
authors: Michailidou
authors: Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), 15706 Santiago de Compostela, Spain.
authors: Ángel
authors: Á
authors: Carracedo
authors: Department of Radiation Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, Canada.
authors: Michael
authors: M
authors: Sia
authors: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Richard
authors: R
authors: Stock
authors: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Nelson N
authors: NN
authors: Stone
authors: Cancer and Other Non-Infectious Diseases, MRC Clinical Trials Unit, London WC2B 6NH, UK.
authors: Matthew R
authors: MR
authors: Sydes
authors: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Jonathan P
authors: JP
authors: Tyrer
authors: Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Shahana
authors: S
authors: Ahmed
authors: Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.
authors: Matthew
authors: M
authors: Parliament
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: Harry
authors: H
authors: Ostrer
authors: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.
authors: Barry S
authors: BS
authors: Rosenstein
authors: Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain; Department of Radiation Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, Canada.
authors: Ana
authors: A
authors: Vega
authors: University of Cambridge, Department of Oncology, Cambridge Biomedical Campus, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors: Neil G
authors: NG
authors: Burnet
authors: Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
authors: Alison M
authors: AM
authors: Dunning
authors: Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK; Department of Oncology, Box 193, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB0 0QQ, UK.
authors: Gillian C
authors: GC
authors: Barnett
authors: Institute of Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK. Electronic address: Catharine.West@manchester.ac.uk.
authors: Catharine M L
authors: CM
authors: West
mesh_terms: D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D011788:Quality of Life; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers
keywords: Cancer survivorship; Genome-wide association study; Prostate cancer; Quality of life; Radiation toxicity; Radiogenomics