Journal
ANNALS OF ONCOLOGY
Volume 26, Issue 4, Pages 756-761Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdv004
Keywords
germline mutation; prostate cancer; hereditary predisposition; homeobox transcription factor gene
Categories
Funding
- Cancer Research UK [C1287/A10118, C12292/A11174]
- European Community [223175 (HEALTH-F2-2009-223175)]
- Cancer Research UK [16565, 10588, 17528, 15007, 19727, 11174] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10096, NF-SI-0509-10242, NF-SI-0611-10106] Funding Source: researchfish
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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. Patients and 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 x 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 x 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 x 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 similar to 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. UK Genetic Prostate Cancer Study: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.
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