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Genetics and Genomics

PALB2 mutations and prostate cancer risk and survival

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.

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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).

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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.

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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 13 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.

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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

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