Abstract
Background
Prostate cancer (PrCa) is one of the most hereditable human cancers, however, only a small fraction of patients has been shown to carry deleterious variants in known cancer predisposition genes.
Methods
Whole-exome sequencing was performed in multiple affected members of 45 PrCa families to select the best candidate genes behind part of the PrCa missing hereditability. Recurrently mutated genes were prioritised, and further investigated by targeted next-generation sequencing in the whole early-onset and/or familial PrCa series of 462 patients.
Results
PRUNE2 stood out from our analysis when also considering the available data on its association with PrCa development. Ten germline pathogenic/likely pathogenic variants in the PRUNE2 gene were identified in 13 patients. The most frequent variant was found in three unrelated patients and identical-by-descent analysis revealed that the haplotype associated with the variant is shared by all the variant carriers, supporting the existence of a common ancestor.
Discussion
This is the first report of pathogenic/likely pathogenic germline variants in PRUNE2 in PrCa patients, namely in those with early-onset/familial disease. Importantly, PRUNE2 was the most frequently mutated gene in the whole series, with a deleterious germline variant identified in 2.8% of the patients, representing a novel prostate cancer predisposition gene.
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Data availability
Data supporting the results reported in this paper can be found at: https://hive.biochemistry.gwu.edu/biomuta/proteinview/P38936 and https://portal.gdc.cancer.gov/.
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Funding
This work was supported by IPO-Porto Research Center (CI-IPOP-16-2012) and by Fundação para a Ciência e a Tecnologia (FCT; PTDC/DTP-PIC/1308/2014—POCI-01-0145-FEDER-016889). The following authors were funded by FCT with scholarships or research contracts: MC (SFRH/BD/116557/2016), SM (SFRH/BD/71397/2010), AB (PTDC/DTP-PIC/1308/2014—POCI-01-0145-FEDER-016889; POCI-01-FEDER-028245; UIDP/DTP/00776/2020; 2021.03835.CEECIND), and PP (PEst-OE/SAU/UI0776/2014; UID/DTP/00776/2013/POCI-01-0145-FEDER-006868; CEECINST/00091/2018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Luis Carvajal-Carmona receives funding from The Auburn Community Cancer Endowed Chair on Basic Science and from the National Cancer Institute of the National Institutes of Health (grant P30CA093373). The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health.
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Conception and design: MT and LGC-C. Data acquisition: MC, SM, PP, AB, RS and NB. Analysis and interpretation of the data: MC, SM, PP, PL and AB. Drafting of the manuscript: MC. Critical revision of the manuscript: MT, PP, LGC-C and AB. Statistical analysis: AB and PL. Funding obtention: MT and LGC-C.
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This study was approved by the Institutional Ethics Committee of the Portuguese Oncology Institute-Porto (approval number: 38.010) and performed in accordance with the Declaration of Helsinki. Written consent was obtained from all participants.
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Cardoso, M., Maia, S., Brandão, A. et al. Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene. Br J Cancer 128, 1077–1085 (2023). https://doi.org/10.1038/s41416-022-02125-6
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DOI: https://doi.org/10.1038/s41416-022-02125-6