Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy

Abstract

Objectives To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor (or HOXB13) gene using DNA samples from 9,559 men with prostate cancer undergoing radical prostatectomy. Patients and Methods DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and confirmed by Sanger sequencing.The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathologic Gleason grade and stage). Results 128 of 9,559 patients were heterozygous carriers of G84E (1.3%).Patients who possessed the variant were more likely to have a family history of prostate cancer (46.0% vs. 35.4% p=0.006).G84E carriers were also more likely diagnosed at a younger age compared to non-carriers (55.2 years vs. 58.1 years; p<0.0001).No difference in the proportion of patients diagnosed with high-grade or advanced stage tumors by carrier status was observed. Conclusion In our study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared to homozygotes for the wild-type allele.No significant differences in allele frequency were detected according to select clinical characteristics of prostate cancer.Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.

The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies

“…(23) However, other studies provide mixed evidence that the mutation is preferentially associated with aggressive clinical features. (9, 10, 13, 21) Furthermore, the mutation frequency reported in this patient population for both prostate cancer cases and men without cancer is in line with prior reports which range from 0.1–1.4% in men without cancer and from 0.1–4.6% in prostate cancer cases. (3–6, 10, 11, 13) The G84E mutation is suspected to be moderately penetrant with variable estimates of cumulative risk of prostate cancer.…”

“…(9, 10, 13, 21) Furthermore, the mutation frequency reported in this patient population for both prostate cancer cases and men without cancer is in line with prior reports which range from 0.1–1.4% in men without cancer and from 0.1–4.6% in prostate cancer cases. (3–6, 10, 11, 13) The G84E mutation is suspected to be moderately penetrant with variable estimates of cumulative risk of prostate cancer. (4, 20) An analysis by MacInnis et al suggests that for a man with the HOXB13 G84E mutation born in 1950, the cumulative risk of prostate cancer is 19% (95% CI=5%–46%) by the time he reaches age 60 and 60% (95% CI=30%–85%) by age 80.…”

“…(4–13, 18–23) The reported estimates of overall risk vary between these studies from 3.3 to 8.8, and with one exception (5), studies report higher estimates for early-onset and familial prostate cancer. A recent meta-analysis of 11 of these studies reported that carriers of the G84E mutation are approximately ~4.5 times more likely to be diagnosed with prostate cancer compared with non-carriers with higher risks among those with early-onset (OR=9.73; 95% CI=6.57–14.39), familial (OR=7.27; 95% CI=4.02–13.15) and aggressive disease (OR=5.81; 95% CI=3.72–9.08).…”

“…Numerous subsequent studies have confirmed this association and suggest furthermore that the mutation is more common among men with early-onset and familial or hereditary prostate cancer. (4–13)…”

Regulating NKX3.1 stability and function: Post-translational modifications and structural determinants

“…Recent studies have shown that HOXB13 is a strong candidate for a familial prostate cancer gene [14,17]. Somatic genetic changes include copy number alterations (such as loss of 8p21, 10p15, 10q21, 13q21, 16q22, 21q22, 22q, and gain of 2p23, 8q24, Xq12), and chromosomal translocations and gene fusions (TMPRSS2:ERG, TMPRSS2:ETV1, TMPRSS2:ETV4, SLC45A3:BRAF) [2][3][4][5][6][7][8][9][10][11][12][13][14]16,[18][19][20][21][22][23][24][25].…”