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.

  • Article
  • Published:

Genetics and Genomics

PALB2 mutations and prostate cancer risk and survival

British Journal of Cancer volume 125, pages 569–575 (2021)Cite this article

Subjects

Abstract

Background

The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers.

Methods

We genotyped 5472 unselected men with prostate cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers.

Results

A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70–2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8–10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57–18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40–4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006).

Conclusion

In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Kaplan–Meier curves of prostate cancer patients with a PALB2 mutation, compared with mutation-negative prostate cancer patients (non-carriers).
Fig. 2: Loss of heterozygosity (LOH) analysis in prostate cancer tissues and normal tissues from four carriers of a PALB2 mutation; retention of the wild-type PALB2 allele is seen in two tumours; two tumours probably have loss of the wild-type PALB2 allele (best shown by asterisks).

Similar content being viewed by others

References

  1. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, 359–386 (2015).

    Article  Google Scholar 

  2. Carter, B. S., Beaty, T. H., Steinberg, G. D., Childs, B. & Walsh, P. C. Mendelian inheritance of familial prostate cancer. Proc. Natl Acad. Sci. USA 89, 3367–3371 (1992).

    Article  CAS  Google Scholar 

  3. Mucci, L. A., Hjelmborg, J. B., Harris, J. R., Czene, K., Havelick, D. J., Scheike, T. et al. Familial risk and heritability of cancer among twins in Nordic countries. JAMA 315, 68–76 (2016).

    Article  CAS  Google Scholar 

  4. Schumacher, F. R., Al Olama, A. A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J. et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat. Genet. 50, 928–936 (2018).

    Article  CAS  Google Scholar 

  5. Ewing, C. M., Ray, A. M., Lange, E. M., Zuhlke, K. A., Robbins, C. M., Tembe, W. D. et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 366, 141–149 (2012).

    Article  CAS  Google Scholar 

  6. Struewing, J. P., Hartge, P., Wacholder, S., Baker, S. M., Berlin, M., McAdams, M. et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 336, 1401–1408 (1997).

    Article  CAS  Google Scholar 

  7. Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J. M., McDonnell, S. K. et al. Mutations in CHEK2 associated with prostate cancer risk. Am. J. Hum. Genet. 72, 270–280 (2003).

    Article  CAS  Google Scholar 

  8. Cybulski, C., Górski, B., Debniak, T., Gliniewicz, B., Mierzejewski, M., Masojć, B. et al. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 64, 1215–1219 (2004).

    Article  CAS  Google Scholar 

  9. Na, R., Zheng, S. L., Han, M., Yu, H., Jiang, D., Shah, S. et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur. Urol. 71, 740–747 (2017).

    Article  CAS  Google Scholar 

  10. Raymond, V. M., Mukherjee, B., Wang, F., Huang, S. C., Stoffel, E. M., Kastrinos, F. et al. Elevated risk of prostate cancer among men with Lynch syndrome. J. Clin. Oncol. 31, 1713–1718 (2013).

    Article  Google Scholar 

  11. Zhang, F., Ma, J., Wu, J., Ye, L., Cai, H., Xia, B. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).

    Article  CAS  Google Scholar 

  12. Reid, S., Schindler, D., Hanenberg, H., Barker, K., Hanks, S., Kalb, R. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

    Article  CAS  Google Scholar 

  13. Yang, X., Leslie, G., Doroszuk, A., Schneider, S., Allen, J., Decker, B. et al. Cancer risks associated with germline PALB2 pathogenic variants: an International Study of 524 Families. J. Clin. Oncol. 38, 674–685 (2020).

    Article  CAS  Google Scholar 

  14. Cybulski, C., Kluźniak, W., Huzarski, T., Wokołorczyk, D., Kashyap, A., Rusak, B. et al. The spectrum of mutations predisposing to familial breast cancer in Poland. Int. J. Cancer 145, 3311–3320 (2019).

    Article  CAS  Google Scholar 

  15. Cybulski, C., Kluźniak, W., Huzarski, T., Wokołorczyk, D., Kashyap, A., Jakubowska, A. et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 16, 638–644 (2015).

    Article  CAS  Google Scholar 

  16. Lener, M. R., Scott, R. J., Kluźniak, W., Baszuk, P., Cybulski, C., Wiechowska-Kozłowska, A. et al. Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer? Int. J. Cancer 139, 601–606 (2016).

    Article  CAS  Google Scholar 

  17. Łukomska, A., Menkiszak, J., Gronwald, J., Tomiczek-Szwiec, J., Szwiec, M., Jasiówka, M. et al. Recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish patients with ovarian cancer. Cancers 13, 849 (2021).

    Article  Google Scholar 

  18. Page, E. C., Bancroft, E. K., Brook, M. N., Assel, M., Battat, M. H. A., Thomas, S. et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers. Eur. Urol. 76, 831–842 (2019).

    Article  CAS  Google Scholar 

  19. Brandão, A., Paulo, P. & Teixeira, M. R. Hereditary predisposition to prostate cancer: from genetics to clinical implications. Int. J. Mol. Sci. 21, https://doi.org/10.3390/ijms21145036 (2020).

  20. Cybulski, C., Carrot-Zhang, J., Kluźniak, W., Rivera, B., Kashyap, A., Wokołorczyk, D. et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat. Genet. 47, 643–646 (2015).

    Article  CAS  Google Scholar 

  21. Cybulski, C., Wokołorczyk, D., Kluźniak, W., Jakubowska, A., Górski, B., Gronwald, J. et al. An inherited NBN mutation is associated with poor prognosis prostate cancer. Br. J. Cancer 108, 461–468 (2013).

    Article  CAS  Google Scholar 

  22. Tischkowitz, M., Sabbaghian, N., Ray, A. M., Lange, E. M., Foulkes, W. D. & Cooney, K. A. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer. Prostate 68, 675–678 (2008).

    Article  Google Scholar 

  23. Pakkanen, S., Wahlfors, T., Siltanen, S., Patrikoski, M., Matikainen, M., Tammela, T. et al. PALB2 variants in hereditary and unselected Finnish Prostate cancer cases. J. Negat. Results Biomed. 8, 12 (2009).

    Article  Google Scholar 

  24. Matejcic, M., Patel, Y., Lilyquist, J., Hu, C., Lee, K. Y., Gnanaolivu, R. D. et al. Pathogenic variants in cancer predisposition genes and prostate cancer risk in men of African ancestry. JCO Precis. Oncol. 4, 32–43 (2020).

    Article  Google Scholar 

  25. Leongamornlert, D. A., Saunders, E. J., Wakerell, S., Whitmore, I., Dadaev, T., Cieza-Borrella, C. et al. Germline DNA repair gene mutations in young-onset prostate cancer cases in the UK: evidence for a more extensive genetic panel. Eur. Urol. 76, 329–337 (2019).

    Article  CAS  Google Scholar 

  26. Southey, M. C., Goldgar, D. E., Winqvist, R., Pylkäs, K., Couch, F., Tischkowitz, M. et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 53, 800–811 (2016).

    Article  CAS  Google Scholar 

  27. Wu, Y., Yu, H., Li, S., Wiley, K., Zheng, S. L., LaDuca, H. et al. Rare germline pathogenic mutations of DNA repair genes are most strongly associated with grade group 5 prostate cancer. Eur. Urol. Oncol. 3, 224–230 (2020).

    Article  Google Scholar 

  28. Pritchard, C. C., Mateo, J., Walsh, M. F., De Sarkar, N., Abida, W., Beltran, H. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

    Article  CAS  Google Scholar 

  29. Leongamornlert, D., Saunders, E., Dadaev, T., Tymrakiewicz, M., Goh, C., Jugurnauth-Little, S. et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br. J. Cancer 110, 1663–1672 (2014).

    Article  CAS  Google Scholar 

  30. Darst, B. F., Dadaev, T., Saunders, E., Sheng, X., Wan, P., Pooler, L. et al. Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa132 (2020).

    Article  Google Scholar 

  31. Heikkinen, T., Kärkkäinen, H., Aaltonen, K., Milne, R. L., Heikkilä, P., Aittomäki, K. et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin. Cancer Res. 15, 3214–3222 (2009).

    Article  CAS  Google Scholar 

  32. Deng, M., Chen, H. H., Zhu, X., Luo, M., Zhang, K., Xu, C. J. et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int. J. Cancer 145, 1517–1528 (2019).

    Article  CAS  Google Scholar 

  33. de Bono, J., Mateo, J., Fizazi, K., Saad, F., Shore, N., Sandhu, S. et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 382, 2091–2102 (2020).

    Article  Google Scholar 

  34. Grellety, T., Peyraud, F., Sevenet, N., Tredan, O., Dohollou, N., Barouk-Simonet, E. et al. Dramatic response to PARP inhibition in a PALB2-mutated breast cancer: moving beyond BRCA. Ann. Oncol. 31, 822–823 (2020).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Daria Zanoza and Ewa Putresza for their help with managing databases.

Members of the Polish Hereditary Prostate Cancer Consortium

Bartłomiej Masojć8, Adam Gołąb9, Bartłomiej Gliniewicz10, Andrzej Sikorski9, Marcin Słojewski9, Jerzy Świtała10, Tomasz Borkowski11, Andrzej Borkowski11, Andrzej Antczak12, Łukasz Wojnar12, Jacek Przybyła13, Marek Sosnowski13, Bartosz Małkiewicz14, Romuald Zdrojowy14, Paulina Sikorska-Radek15, Józef Matych15, Jacek Wilkosz16, Waldemar Różański16, Jacek Kiś17, Krzysztof Bar17, Piotr Bryniarski18, Andrzej Paradysz18, Konrad Jersak19, Jerzy Niemirowicz19, Piotr Słupski20, Piotr Jarzemski20, Michał Skrzypczyk21, Jakub Dobruch21, Michał Puszyński9, Michał Soczawa9, Mirosław Kordowski10, Marcin Życzkowski18, Andrzej Borówka21, Joanna Bagińska22, Kazimierz Krajka22, Małgorzata Stawicka23, Olga Haus24, Hanna Janiszewska24, Agnieszka Stembalska25, Maria Małgorzata Sąsiadek25.

Author information

Authors and Affiliations

  1. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland

    Dominika Wokołorczyk, Wojciech Kluźniak, Klaudia Stempa, Bogna Rusak, Tomasz Huzarski, Jacek Gronwald, Katarzyna Gliniewicz, Aniruddh Kashyap, Sylwia Morawska, Tadeusz Dębniak, Anna Jakubowska, Jan Lubiński & Cezary Cybulski

  2. Department of Clinical Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland

    Tomasz Huzarski

  3. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland

    Anna Jakubowska

  4. Clinics of Oncology, University Hospital in Zielona Góra, Zielona Góra, Poland

    Marek Szwiec

  5. Department of Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland

    Paweł Domagała

  6. Women’s College Research Institute, Women’s College Hospital, University of Toronto, Toronto, Canada

    Steven A. Narod & Mohammad R. Akbari

  7. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada

    Steven A. Narod & Mohammad R. Akbari

  8. West Pomeranian Oncology Center, Szczecin, Poland

    Bartłomiej Masojć

  9. Clinic of Urology, Pomeranian Medical University, Szczecin, Poland

    Adam Gołąb, Andrzej Sikorski, Marcin Słojewski, Michał Puszyński & Michał Soczawa

  10. Division of Urology, Maria Skłodowska-Curie Hospital, Szczecin, Poland

    Bartłomiej Gliniewicz, Jerzy Świtała & Mirosław Kordowski

  11. Department of Urology, Medical University, Warszawa, Poland

    Tomasz Borkowski & Andrzej Borkowski

  12. Chair of Urology, Medical University, Poznań, Poland

    Andrzej Antczak & Łukasz Wojnar

  13. Department of Urology, Medical University of Lódź, Łódź, Poland

    Jacek Przybyła & Marek Sosnowski

  14. Department of Urology and Urological Oncology, University of Medicine, Wrocław, Poland

    Bartosz Małkiewicz & Romuald Zdrojowy

  15. Division of Urology, Regional Hospital, Łódź, Poland

    Paulina Sikorska-Radek & Józef Matych

  16. Second Department of Urology, Medical University of Lódź, Łódź, Poland

    Jacek Wilkosz & Waldemar Różański

  17. Department of Urology, University Hospital of Lublin, Lublin, Poland

    Jacek Kiś & Krzysztof Bar

  18. Department of Urology, Medical University of Silesia, Zabrze, Poland

    Piotr Bryniarski, Andrzej Paradysz & Marcin Życzkowski

  19. Department of Urology, Ministry of Internal Affairs and Administration Hospital, Łódź, Poland

    Konrad Jersak & Jerzy Niemirowicz

  20. Department of Urology, J. Biziel Hospital, Bydgoszcz, Poland

    Piotr Słupski & Piotr Jarzemski

  21. Department of Urology, Centre of Postgraduate Urology Education, Warszawa, Poland

    Michał Skrzypczyk, Jakub Dobruch & Andrzej Borówka

  22. Clinic of Urology, Medical University, Gdańsk, Poland

    Joanna Bagińska & Kazimierz Krajka

  23. Department of Clinical Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland

    Małgorzata Stawicka

  24. Department of Clinical Genetics, Nicolaus Copernicus University, Bydgoszcz, Poland

    Olga Haus & Hanna Janiszewska

  25. Department of Genetics, Wroclaw Medical University, Wrocław, Poland

    Agnieszka Stembalska & Maria Małgorzata Sąsiadek

Authors
  1. Dominika Wokołorczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wojciech Kluźniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klaudia Stempa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bogna Rusak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomasz Huzarski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jacek Gronwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katarzyna Gliniewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aniruddh Kashyap
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sylwia Morawska
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tadeusz Dębniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna Jakubowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marek Szwiec
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Paweł Domagała
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jan Lubiński
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mohammad R. Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Cezary Cybulski
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the Polish Hereditary Prostate Cancer Consortium

  • Bartłomiej Masojć
  • , Adam Gołąb
  • , Bartłomiej Gliniewicz
  • , Andrzej Sikorski
  • , Marcin Słojewski
  • , Jerzy Świtała
  • , Tomasz Borkowski
  • , Andrzej Borkowski
  • , Andrzej Antczak
  • , Łukasz Wojnar
  • , Jacek Przybyła
  • , Marek Sosnowski
  • , Bartosz Małkiewicz
  • , Romuald Zdrojowy
  • , Paulina Sikorska-Radek
  • , Józef Matych
  • , Jacek Wilkosz
  • , Waldemar Różański
  • , Jacek Kiś
  • , Krzysztof Bar
  • , Piotr Bryniarski
  • , Andrzej Paradysz
  • , Konrad Jersak
  • , Jerzy Niemirowicz
  • , Piotr Słupski
  • , Piotr Jarzemski
  • , Michał Skrzypczyk
  • , Jakub Dobruch
  • , Michał Puszyński
  • , Michał Soczawa
  • , Mirosław Kordowski
  • , Marcin Życzkowski
  • , Andrzej Borówka
  • , Joanna Bagińska
  • , Kazimierz Krajka
  • , Małgorzata Stawicka
  • , Olga Haus
  • , Hanna Janiszewska
  • , Agnieszka Stembalska
  •  & Maria Małgorzata Sąsiadek

Contributions

D.W. designed the study, analysed the study data and drafted the manuscript. W.K., K.S., B.R., K.G. and S.M. selected and prepared DNA samples for genotyping and performed genotyping. T.H., J.G., T.D., M.S. and C.C. enrolled patients and controls for the study, and collected phenotypic data for the study. A.K. performed statistical analyses. W.K. and A.J. performed NGS sequencing. P.D. selected, prepared and provided tissue samples and performed LOH analysis. M.R.A. performed bioinformatics analysis of NGS sequencing data and assisted in drafting the manuscript. S.A.N. and J.L. assisted in coordination of the study and in drafting the manuscript. C.C. conceived, designed and coordinated the study and assisted in drafting the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Cezary Cybulski.

Ethics declarations

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin (IRB No. KB-0012/97/17). Patient clinical data have been obtained in a manner conforming with IRB ethical guidelines. Informed consent was obtained from all individual participants included in the study.

Data availability

The main research data supporting the results of this study are included in Tables 1–3 and Figs. 1 and 2. Other data can be made available upon reasonable request from the corresponding author.

Competing interests

S.N. is an editorial board member for the British Journal of Cancer. All other authors declare no competing interests.

Funding information

This study was funded by National Science Centre, Poland; project number: 2015/19/B/NZ2/02439.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wokołorczyk, D., Kluźniak, W., Stempa, K. et al. PALB2 mutations and prostate cancer risk and survival. Br J Cancer 125, 569–575 (2021). https://doi.org/10.1038/s41416-021-01410-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01410-0

This article is cited by

Search

Advanced search

Quick links