title: Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.
abstract: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy.
  
  
  
  The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods.
  
  
  
  A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity.
  
  
  
  Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.
authors.affiliation: The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, 123 Old Brompton Road, London SW7 3RP, UK.
authors.forename: Mahbubl
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
authors.forename: Leila
authors.initials: L
authors.lastname: Dorling
authors.affiliation: Department of Radiation Oncology, University of Rochester Medical Centre, Saunders Research Building, 265 Crittenden Boulevard, Rochester, NY 14620, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kerns
authors.affiliation: Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.|Genomic Medicine Group, CIBERER, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Fachal
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.affiliation: Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Matt
authors.initials: M
authors.lastname: Partliament
authors.affiliation: Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Rosenstein
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
authors.affiliation: Department of Radiation Oncology, USC University Hospital Complex, SERGAS, Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gómez-Caamaño
authors.affiliation: Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
authors.forename: Gill
authors.initials: G
authors.lastname: Barnett
authors.affiliation: The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, 123 Old Brompton Road, London SW7 3RP, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Dearnaley
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.affiliation: Clinical Trials Unit (CTU), Medical Research Council, London WC2B 6NH, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Sydes
authors.affiliation: Department of Oncology, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Burnet
authors.affiliation: Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, 123 Old Brompton Road, London SW7 3RP, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK.
authors.forename: Catharine M L
authors.initials: CM
authors.lastname: West
mesh_terms: D000368:Aged; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000453:epidemiology*; D044465:White People / Q000235:genetics