These results indicate that risk alleles of HOXB13 and common variant SNPs are important components of inherited PCa risk in the Norwegian population, although these factors appear to contribute little to the malignancy's aggressiveness.
Association with PCa risk was statistically significant for variants in BRCA2 (P < 0.001, OR = 5.65, 95% CI = 3.55-9.32), HOXB13 (P < 0.001, OR = 4.73, 95% CI = 2.84-8.19), and ATM (P < 0.001, OR = 2.86, 95% CI = 1.63-5.15).
Unsupervised Principal Component Analysis (PCA) led to a focused core HOXB13 target gene-set referred to as HOTPAM9 (HOXB13 Targets separating Primary And Metastatic PCs).
For example, a recent study suggested that one cannot adequately impute the HOXB13G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project).
Most notably, HOXB13 and BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease.
Collaborative investigations using next-generation sequencing to identify genetic variants associated with prostate cancer risk have revealed the significance of HOXB13, BRCA 1/2, and DNA repair mutations.
We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
In addition to the loss of HOXB13 expression, maintaining AR may be an important step for prostate cancer cells to tolerate the suppressor function of HOXB13.
In conclusion, the G84E mutation of HOXB13, a relatively recent mutation that likely occurred in Northern Europe, significantly increases risk for PCa.
This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency.
Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (rs138213197" genes_norm="10481">G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele.
HOXB13G84E was observed in 1.3% of population controls and was strongly associated with prostate cancer risk (CAPS: odds ratio [OR]: 3.4; 95% confidence interval [CI], 2.2-5.4; Stockholm-1: OR: 3.5; 95% CI, 2.4-5.2).