title: Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.
abstract: BACKGROUND
  A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country.
  
  
  METHODS
  This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study.
  
  
  RESULTS
  HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population.
  
  
  CONCLUSIONS
  The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk.
  Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172.
  Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.
authors.affiliation: Institute of Cancer Research, London. Electronic address: zsofia.kote-jarai@icr.ac.uk.
authors.forename: Z
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Institute of Cancer Research, London.
authors.forename: C
authors.initials: C
authors.lastname: Mikropoulos
authors.affiliation: Institute of Cancer Research, London.
authors.forename: D A
authors.initials: DA
authors.lastname: Leongamornlert
authors.affiliation: Institute of Cancer Research, London.
authors.forename: T
authors.initials: T
authors.lastname: Dadaev
authors.affiliation: Institute of Cancer Research, London.
authors.forename: M
authors.initials: M
authors.lastname: Tymrakiewicz
authors.affiliation: Institute of Cancer Research, London.
authors.forename: E J
authors.initials: EJ
authors.lastname: Saunders
authors.affiliation: Institute of Cancer Research, London.
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.affiliation: Institute of Cancer Research, London.
authors.forename: S
authors.initials: S
authors.lastname: Jugurnauth-Little
authors.affiliation: Institute of Cancer Research, London.
authors.forename: K
authors.initials: K
authors.lastname: Govindasami
authors.affiliation: Institute of Cancer Research, London.
authors.forename: M
authors.initials: M
authors.lastname: Guy
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford; Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford.
authors.forename: F C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol.
authors.forename: J L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge.
authors.forename: D E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge.
authors.forename: J A
authors.initials: JA
authors.lastname: Lane
authors.affiliation: Institute of Cancer Research, London.
authors.forename: D
authors.initials: D
authors.lastname: Dearnaley
authors.affiliation: Institute of Cancer Research, London.
authors.forename: R A
authors.initials: RA
authors.lastname: Wilkinson
authors.affiliation: Institute of Cancer Research, London.
authors.forename: E J
authors.initials: EJ
authors.lastname: Sawyer
authors.affiliation: Institute of Cancer Research, London.
authors.forename: A
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge.
authors.forename: A C
authors.initials: AC
authors.lastname: Antoniou
authors.affiliation: Institute of Cancer Research, London; The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Eeles
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011379:Prognosis; D011467:Prostate / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D015996:Survival Rate; D006113:United Kingdom
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; D017430:Prostate-Specific Antigen
keywords: germline mutation; hereditary predisposition; homeobox transcription factor gene; prostate cancer