751O - Prevalence of HOXB13G84E germline mutation in UK prostate cancer cases; correlation with tumour characteristics and outcomes

Date 27 September 2014
Event ESMO 2014
Session Genetic predisposition to cancer
Topics Prostate Cancer
Cancer Aetiology, Epidemiology, Prevention
Familial Cancer
Presenter Christos Mikropoulos
Citation Annals of Oncology (2014) 25 (suppl_4): iv254-iv254. 10.1093/annonc/mdu335
Authors C. Mikropoulos1, T. Dadaev1, M. Tymrakiewicz1, D. Leongamornlert1, E. Saunders1, S.J. Little1, K. Govindasami1, M. Guy1, R. Wilkinson1, A. Morgan1, J. Donovan2, D. Neal3, F. Hamdy4, A. Antoniou5, R. Eeles6, Z. Kote-Jarai1
  • 1Cancer Genetics, The Institute of Cancer Research ICR, SM2 5NG - Sutton/GB
  • 2School Of Social And Community Medicine, University of Bristol, Bristol/GB
  • 3Urology, University of Cambridge, Cambridge/GB
  • 4Faculty Of Medical Sciences, Nuffiend Department of Surgical Sciences, Oxford/GB
  • 5Epidemiology, University of Cambridge, Cambridge/GB
  • 6Oncogenetics Team, The Institute of Cancer Research ICR, GB-SM2 5NG - Sutton/GB

Abstract

Aim

A rare recurrent missense variant in HOXB13 rs 138213197 is associated with hereditary prostate cancer (PrCa). The frequency of this variant varies between different geographic regions. We performed a case-control study in the UK population to assess the prevalence of this variant and its implications on PrCa risk and tumour characteristics.

Methods

We screened 8652 white Caucasian men from 3 UKGPCS (United Kingdom Prostate Cancer Genetic) studies and 5252 population based controls from the ProtecT study. Germline blood DNA was genotyped for G84E (rs13821397) using a custom made TaqMan assay. 2 duplicate samples and 4 positive and 4 negative controls were included on each 384 well plate.Concordance for the control samples was >99%.

Results

HOXB13 rs138213197 was identified in 0.5% of healthy controls and in 1.6% of PrCa cases. The Odds Ratio (OR) was 2.93 for increased risk of developing prostate cancer and the association was stronger for cases with family history with an OR = 4.53 and young onset PrCa (diagnosed under the age of 55) with an OR = 3.1. Multivariate analysis showed no association with Gleason score, presenting PSA, TNM stage or NCCN risk score. The biochemical relapse rate was not higher for carriers. We found no evidence of interaction between this rare variant and a Polygenic Risk Score (PRS) based on common variants consisting of 71 single nucleotide polymorphisms (SNPs). As a result men with the mutation in the highest quintile of the PRS have a 5-fold higher PrCa risk compared to those in the third quintile.

Conclusions

HOXB13G84E is a highly penetrant, rare genetic predisposition variant linked with young onset and familial PrCa. No assocation with an aggressive phenotype was found. The clinical application of this finding in genetic PrCa screening modelling is still unclear. Based on the estimated incidence this variant accounts for approxiately 1% of the familial PrCa risk in the UK population.

Disclosure

All authors have declared no conflicts of interest.