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Homeobox B13 G84E Mutation and Prostate Cancer Risk.
Eur Urol. 2019 05; 75(5):834-845.EU

Abstract

BACKGROUND

The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain.

OBJECTIVE

To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors.

DESIGN, SETTING, AND PARTICIPANTS

Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort.

RESULTS AND LIMITATIONS

A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history.

CONCLUSIONS

PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort.

PATIENT SUMMARY

Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. 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.

Authors+Show Affiliations

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Electronic address: ten25@medschl.cam.ac.uk.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.No affiliation info availableOncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

Language

eng

PubMed ID

30527799

Citation

Nyberg, Tommy, et al. "Homeobox B13 G84E Mutation and Prostate Cancer Risk." European Urology, vol. 75, no. 5, 2019, pp. 834-845.
Nyberg T, Govindasami K, Leslie G, et al. Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur Urol. 2019;75(5):834-845.
Nyberg, T., Govindasami, K., Leslie, G., Dadaev, T., Bancroft, E., Ni Raghallaigh, H., Brook, M. N., Hussain, N., Keating, D., Lee, A., McMahon, R., Morgan, A., Mullen, A., Osborne, A., Rageevakumar, R., Kote-Jarai, Z., Eeles, R., & Antoniou, A. C. (2019). Homeobox B13 G84E Mutation and Prostate Cancer Risk. European Urology, 75(5), 834-845. https://doi.org/10.1016/j.eururo.2018.11.015
Nyberg T, et al. Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur Urol. 2019;75(5):834-845. PubMed PMID: 30527799.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homeobox B13 G84E Mutation and Prostate Cancer Risk. AU - Nyberg,Tommy, AU - Govindasami,Koveela, AU - Leslie,Goska, AU - Dadaev,Tokhir, AU - Bancroft,Elizabeth, AU - Ni Raghallaigh,Holly, AU - Brook,Mark N, AU - Hussain,Nafisa, AU - Keating,Diana, AU - Lee,Andrew, AU - McMahon,Romayne, AU - Morgan,Angela, AU - Mullen,Andrea, AU - Osborne,Andrea, AU - Rageevakumar,Reshma, AU - ,, AU - Kote-Jarai,Zsofia, AU - Eeles,Rosalind, AU - Antoniou,Antonis C, Y1 - 2018/12/08/ PY - 2018/04/23/received PY - 2018/11/08/accepted PY - 2018/12/12/pubmed PY - 2018/12/12/medline PY - 2018/12/12/entrez KW - Genetic risk KW - HomeoboxB13 KW - Kin-cohort study KW - Meta-analysis KW - Prostate cancer SP - 834 EP - 845 JF - European urology JO - Eur. Urol. VL - 75 IS - 5 N2 - BACKGROUND: The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain. OBJECTIVE: To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. DESIGN, SETTING, AND PARTICIPANTS: Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort. RESULTS AND LIMITATIONS: A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history. CONCLUSIONS: PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort. PATIENT SUMMARY: Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. 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. SN - 1873-7560 UR - https://www.unboundmedicine.com/medline/citation/30527799/Homeobox_B13_G84E_Mutation_and_Prostate_Cancer_Risk_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0302-2838(18)30872-8 DB - PRIME DP - Unbound Medicine ER -