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Article of the Week: Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness

Tine M. Storebjerg*,†,‡, Søren Høyer†, Pia Kirkegaard§, Flemming Bro§, the LuCamp Study Group, Torben F. Ørntoft‡, Michael Borre* and Karina D. Sørensen‡

 

Departments of*Urology †Pathology, Aarhus University Hospital, ‡Department of Molecular Medicine, Aarhus University Hospital, §Research Unit for General Practice and Research Centre for Cancer Diagnosis in Primary Care, Aarhus University, Aarhus, and Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care, Copenhagen, Denmark

 

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Objectives

To determine the prevalence of the HOXB13 G84E mutation (rs138213197) in Danish men with or without prostate cancer (PCa) and to investigate possible correlations between HOXB13 mutation status and clinicopathological characteristics associated with tumour aggressiveness.

Materials and Methods

We conducted a case–control study including 995 men with PCa (cases) who underwent radical prostatectomy (RP) between 1997 and 2011 at the Department of Urology, Aarhus University Hospital, Denmark. As controls, we used 1622 healthy men with a normal prostate specific antigen (PSA) level.

Results

The HOXB13 G84E mutation was identified in 0.49% of controls and in 2.51% of PCa cases. The mutation was associated with a 5.12-fold increased relative risk (RR) of PCa (95% confidence interval [CI] 2.26–13.38; P = 13 × 10−6). Furthermore, carriers of the risk allele were significantly more likely to have a higher PSA level at diagnosis (mean PSA 19.9 vs 13.6 ng/mL; P = 0.032), a pathological Gleason score ≥7 (83.3 vs 60.9%; P = 0.032), and positive surgical margins (56.0 vs 28.5%; P = 0.006) than non-carriers. Risk allele carriers were also more likely to have aggressive disease (54.2 vs 28.6%; P = 0.011), as defined by a preoperative PSA ≥20 ng/mL, pathological Gleason score ≥ (4+3) and/or presence of regional/distant disease. At a mean follow-up of 7 months, we found no significant association between HOXB13mutation status and biochemical recurrence in this cohort of men who underwent RP.

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Conclusions

This is the first study to investigate the HOXB13 G84E mutation in Danish men. The mutation was detected in 0.49% of controls and in 2.51% of cases, and was associated with 5.12-fold increased RR of being diagnosed with PCa. In our RP cohort, HOXB13 mutation carriers were more likely to develop aggressive PCa. Further studies are needed to assess the potential of HOXB13 for future targeted screening approaches.

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Editorial: HOXB13 mutations and prostate cancer risk

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For the first time, Storebjerg et al. [1] describe the prevalence of the HOXB13 G84E mutation in a Danish population and its association with prostate cancer risk and features indicative of clinically aggressive disease in a cohort of men undergoing radical prostatectomy. In this study, the prostate cancer risk mutation was seen in 0.49% of controls with an ~5-fold increase in risk of prostate cancer among carriers. The homeobox transcription factor gene HOXB13, is located on the long arm of chromosome 17 (17q21), and belongs to a superfamily of genes considered critical to animal embryonic development, characterised by a highly-conserved DNA-binding domain. In 2012, our research team described the association of a rare recurrent HOXB13 mutation, substituting adenine for guanine in the second position of codon 84 resulting in the replacement of glycine by glutamic acid, with prostate cancer and found that the carrier frequency was ~20-times higher among men with early onset disease and multiple affected close relatives compared with men presumed without disease [2]. Since then, numerous studies have confirmed this association with estimates of risk overall varying from ~3 to 9-fold, and generally a greater risk seen among men diagnosed before the age of 60 years and among those with a positive family history of disease among first-degree relatives [3]. The G84E mutation is almost exclusively found in men of Northern European descent with evidence suggesting that it is a relatively recent (circa 1790s) founder mutation in the population, and considered to be of moderate penetrance (estimated lifetime risk among carriers 35–65%) [4]. The same germline mutation has also been preliminarily reported to be associated with cancers of the breast, colon, bladder, and leukaemia, but requires further investigation [5, 6].

The findings from this study [1], both for the prevalence of the mutation, as well as its magnitude of association with prostate cancer, are comparable to prior reports in Northern European populations. Furthermore, among the 995 cases, the mutation frequency was significantly associated with features predictive of progression after surgery (high PSA level, positive surgical margins, higher pathological Gleason score, and non-organ confined disease) suggesting that genetic evaluation of men with a strong family history would identify a subset of men that would benefit from early screening and intervention in the same manner as are male carriers of known founder mutations in BRCA2[7]. The observation between HOXB13 and clinical features indicative of aggressive disease has been less consistent compared with studies of risk overall and the exact mechanism whereby the gene contributes to malignant progression in the prostate is not well-understood. There is some suggestion that the gene may operate both as a tumour suppressor, as early studies reported its suppression of androgen receptor activity, and as an oncogene as HOXB13 overexpression has been seen in androgen-independent tumours [8].

Currently, most countries (including the USA) do not recommend use of PSA screening for men at average risk for prostate cancer. However, given the significant risk of prostate cancer in men carrying a single copy of the HOXB13 G84E allele, should these male mutation carriers be screened for prostate cancer with PSA testing and DRE? If so, how do we identify these men and at what age should testing commence? Unfortunately, many G84E carriers may not be identified by family history, which raises the question about when is the risk of disease significant enough to warrant population level testing? As Nordic countries, including Denmark, have a higher frequency of HOXB13 G84E allele in the general population, research directed toward understanding the benefit of genetic testing followed by prostate cancer early detection strategies should be considered.

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Kathleen A. Cooney* and Jennifer L. Beebe-Dimmer†

 

*Departments of Internal Medicine and Urology, The University of Michigan, Comprehensive Cancer Center, Ann Arbor, and †Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detro it, MI, USA

 

References

 

1 Storebjerg TM, Høyer S, Kirkegaard P et al. Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness. BJU Int 2016; 118: 646–53

 

2 Ewing CM, Ray AM, Lange EM et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 141–9

 

3 Beebe-Dimmer JL, Isaacs WB, Zuhlke KA et al. Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy. BJU Int 2014; 113: 830–5

 

4 Chen Z, Greenwood C, Isaacs WB et al. The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the reduce trial. Carcinogenesis 2013; 34: 1260–4

 

5 Alanee S, Couch F, OffitK. Association of a HOXB13 variant with breast cancer. N Engl J Med 2012; 367: 480–1

 

6 Beebe-Dimmer JL, Hathcock M, Yee C et al. The HOXB13 G84E mutation is associated with an increased risk for prostate cancer and other malignancies. Cancer Epidemiol Biomarkers Prev 2015; 24: 1366–72

 

7 National Comprehensive Cancer Network (NCCN), NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2015). Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 12-27-2015

 

8 Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 2010; 10: 361–71

 

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