Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Case Study
  • Published:

Familial prostate cancer: the damage done and lessons learnt

Nature Reviews Urology volume 10, pages 116–122 (2013)Cite this article

Subjects

Abstract

Background. A 51-year-old French Canadian man presented to his family physician owing to an extensive family history of prostate cancer in five brothers, his father and two paternal uncles. His serum PSA level was 4.9 ng/ml and a six-core biopsy revealed the presence of a prostate adenocarcinoma with a Gleason score of 7 (3+4). He was treated with radical prostatectomy. Repeat PSA tests revealed a gradual rise in PSA levels despite androgen deprivation therapy with bicalutamide and goserelin over the course of 3 years. Genetic evaluation was undertaken in view of his personal and family history. The proband died at the age of 58 years of widespread metastasis.

Investigations. PSA testing, six-core biopsy, genetic counselling and mutation analysis for French Canadian founder mutations in the BRCA1 and BRCA2 genes, histopathological review of tumour tissue from family members, examination of loss of heterozygosity at the BRCA2 gene locus, immunohistochemistry to determine the expression of the ERG nuclear oncoprotein in prostate tumours, genotyping with eight selected risk-associated single nucleotide polymorphisms, Doppler ultrasonography of the leg, CT of the abdomen and pelvis with intravenous and oral contrast, chest CT with intravenous contrast for the assessment of metastatic prostate cancer, genetic testing for the G84E variant in the HOXB13 gene.

Diagnosis. Early-onset and aggressive prostate cancer associated with a nonsense French Canadian BRCA2 founder mutation, c.5857G>T (p.Glu1953*).

Management. Radical prostatectomy, hormone therapy with bicalutamide and goserelin, palliative chemotherapy initially with docetaxel plus prednisone then with mitoxantrone plus prednisone, as well as genetic counselling and testing for the proband and his family members.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pedigree analysis of a family affected by hereditary prostate cancer.
Figure 2: Histology of prostate tissue that harbours the familial BRCA2 mutation (from individual III-6).

References

  1. Tonin, P. N. et al. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am. J. Hum. Genet. 63, 1341–1451 (1998).

    Article  CAS  Google Scholar 

  2. Tonin, P. N. et al. Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history. Int. J. Cancer 95, 189–193 (2001).

    Article  CAS  Google Scholar 

  3. Osher, D. J. et al. Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br. J. Cancer 106, 1460–1463 (2012).

    Article  CAS  Google Scholar 

  4. Lathrop, G. M., Lalouel, J. M., Juliel, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl Acad. Sci. USA 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  5. Edwards, S. M. et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am. J. Hum. Genet. 72, 1–12 (2003).

    Article  CAS  Google Scholar 

  6. Eeles, R. A. et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41, 1116–1121 (2009).

    Article  CAS  Google Scholar 

  7. Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

    Article  CAS  Google Scholar 

  8. Al Olama, A. A. et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 41, 1058–1060 (2009).

    Article  CAS  Google Scholar 

  9. Eeles, R. A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).

    Article  CAS  Google Scholar 

  10. Ewing, C. M. et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 366, 141–149 (2012).

    Article  CAS  Google Scholar 

  11. Canadian Cancer Society. Canadian Cancer Statistics 2011 [online], (2011).

  12. Welch, H. G. & Albertsen, P. C. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986–2005. J. Natl Cancer Inst. 101, 1325–1329 (2009).

    Article  Google Scholar 

  13. Lin, D. W., Porter, M. & Montgomery, B. Treatment and survival outcomes in young men diagnosed with prostate cancer: a population based cohort study. Cancer 115, 2863–2871 (2009).

    Article  Google Scholar 

  14. Schaid, D. J. The complex genetic epidemiology of prostate cancer. Hum. Mol. Genet. 13, R103–R121 (2004).

    Article  CAS  Google Scholar 

  15. Carter, B. S. et al. Hereditary prostate cancer: epidemiologic and clinical features. J. Urol. 150, 797–802 (1993).

    Article  CAS  Google Scholar 

  16. Grönberg, H., Damber, L., Damber, J. E. & Iselius, L. Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am. J. Epidemiol. 146, 552–557 (1997).

    Article  Google Scholar 

  17. Schaid, D. J., McDonnell, S. K., Blute, M. L. & Thibodeau, S. N. Evidence for autosomal dominant inheritance of prostate cancer. Am. J. Hum. Genet. 62, 1425–1438 (1998).

    Article  CAS  Google Scholar 

  18. Verhage, B. A. et al. Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57, 97–101 (2001).

    Article  CAS  Google Scholar 

  19. Smith, J. R. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274, 1371–1374 (1996).

    Article  CAS  Google Scholar 

  20. Xu, J. et al. Linkage of prostate cancer susceptibility loci to chromosome 1. Hum. Genet. 108, 335–345 (2001).

    Article  CAS  Google Scholar 

  21. Berthon, P. et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am. J. Hum. Genet. 62, 1416–1424 (1998).

    Article  CAS  Google Scholar 

  22. Gibbs, M. et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am. J. Hum. Genet. 64, 776–787 (1999).

    Article  CAS  Google Scholar 

  23. Xu, J. et al. A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am. J. Hum. Genet. 77, 219–229 (2005).

    Article  CAS  Google Scholar 

  24. Varghese, J. S. & Easton, D. F. Genome-wide association studies in common cancers—what have we learnt? Curr. Opin. Genet. Dev. 20, 201–209 (2010).

    Article  CAS  Google Scholar 

  25. The Breast Cancer linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).

  26. Willems, A. J. et al. Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin. Cancer Res. 14, 2953–2961 (2008).

    Article  CAS  Google Scholar 

  27. Mitra, A. et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br. J. Cancer 98, 502–507 (2008).

    Article  CAS  Google Scholar 

  28. Narod, S. A. et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br. J. Cancer 99, 371–374 (2008).

    Article  CAS  Google Scholar 

  29. Edwards, S. M. et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br. J. Cancer 103, 918–924 (2010).

    Article  CAS  Google Scholar 

  30. Thorne, H. et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev. Res. 4, 1002–1010 (2011).

    Article  CAS  Google Scholar 

  31. Sigurdsson, S. et al. BRCA2 mutation in Icelandic prostate cancer patients. J. Mol. Med. 75, 758–761 (1997).

    Article  CAS  Google Scholar 

  32. Tryggvadóttir, L. et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J. Natl Cancer Inst. 99, 929–935 (2007).

    Article  Google Scholar 

  33. Gallagher, D. J. et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin. Cancer Res. 16, 2115–2121 (2010).

    Article  CAS  Google Scholar 

  34. Grönberg, H. et al. BRCA2 mutation in a family with hereditary prostate cancer. Genes Chromosomes Cancer 30, 299–301 (2001).

    Article  Google Scholar 

  35. Li, C. et al. Identification of two distinct deleted regions on chromosome 13 in prostate cancer. Oncogene 16, 481–487 (1998).

    Article  CAS  Google Scholar 

  36. Gudmundsson, J. et al. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12–13. Cancer Res. 55, 4830–4832 (1995).

    CAS  PubMed  Google Scholar 

  37. Vanaja, D. K., Cheville, J. C., Iturria, S. J. & Young C. Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  38. Park, K. et al. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12, 590–598 (2010).

    Article  CAS  Google Scholar 

  39. Prostate Cancer Canada. Prostate Cancer Canada—Early Detection Guideline [online], (2010).

  40. Schröder, F. H. et al. Screening and prostate-cancer mortality in a randomized European study. N. Engl. J. Med. 360, 1320–1328 (2009).

    Article  Google Scholar 

  41. Mitra, A. V. et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. 107, 28–39 (2011).

    Article  Google Scholar 

  42. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

    Article  CAS  Google Scholar 

  43. Petrylak, D. P. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351, 1513–1520 (2004).

    Article  CAS  Google Scholar 

  44. Gallagher, D. J. et al. Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer. BJU Int. 109, 713–719 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to the proband and his family members for their contributions to this Case Study. The work was supported by funds provided by Drs Armen Aprikian and Franck Bladou, Division of Urology, McGill University, and by a subcontract to the NIH Grant # 5U01CA089600-09 [International Consortium on Prostate Cancer Genetics (ICPCG), PI: William Isaacs].

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Research Institute of McGill University Health Centre, Montreal, H3G 1A4, QC, Canada

    Nassim Taherian & Nancy Hamel

  2. Division of Anatomic Pathology, Hôpital du Sacré-Cœur de Montréal, Montreal, H4J 1C5, QC, Canada

    Louis R. Bégin

  3. Department of Pathology and Laboratory Medicine and Oncology, University of Calgary and Southern Alberta Cancer Institute, Calgary, T2V 1P9, AB, Canada

    Tarek A. Bismar

  4. Department of Dermatology, University of Utah School of Medicine, Salt Lake City, 84132, UT, USA

    David E. Goldgar & Bing-Jian Feng

  5. Department of Oncology and Human Genetics, Program in Cancer Genetics, McGill University, Montreal, H2W 1S6, QC, Canada

    William D. Foulkes

Authors
  1. Nassim Taherian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy Hamel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louis R. Bégin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tarek A. Bismar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David E. Goldgar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bing-Jian Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N. Taherian researched data for and wrote this article. All authors made a substantial contribution to discussion of content and review of the manuscript before submission.

Corresponding author

Correspondence to William D. Foulkes.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Liability classes (DOC 46 kb)

Supplementary Table 2

Total number of risk alleles and genotype score weighted by the logarithmic of the odds (LOD) ratio for 8 different SNPs (DOC 58 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taherian, N., Hamel, N., Bégin, L. et al. Familial prostate cancer: the damage done and lessons learnt. Nat Rev Urol 10, 116–122 (2013). https://doi.org/10.1038/nrurol.2012.257

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2012.257

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer