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Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene

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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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Fig. 1: Pedigrees of WES families carrying unique PRUNE2 variants.
Fig. 2: Pedigrees of the patients carrying the recurrent PRUNE2 splicing variant, c.509-2A>G.
Fig. 3: IBD analysis for carriers of the splicing variant c.509-2A>G.
Fig. 4: Mutation map showing the predicted localisation of the identified PRUNE2 variants in PRUNE2 protein.

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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/.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin. 2021. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  2. Brandão A, Paulo P, Teixeira M. Hereditary predisposition to prostate cancer: from genetics to clinical implications. Int J Mol Sci. 2020;21:1–23.

    Article  Google Scholar 

  3. Bruner D, Moore D, Parlanti A, Dorgan JPE. Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis. Int J Cancer. 2003;107:797–803.

    Article  CAS  PubMed  Google Scholar 

  4. Brandt A, Bermejo J, Sundquist J, Hemminki K. Age at diagnosis and age at death in familial prostate cancer. Oncologist. 2009;14:1209–17.

    Article  PubMed  Google Scholar 

  5. Verhage BAJ, Baffoe-Bonnie AB, Baglietto L, Smith DS, Bailey-Wilson JE, Beaty TH, et al. Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology. 2001;57:97–101.

    Article  CAS  PubMed  Google Scholar 

  6. Verhage BAJ, Aben KKH, Witjes JA, Straatman H, Schalken JA, Kiemeney LALM. Site-specific familial aggregation of prostate cancer. Int J Cancer. 2004;109:611–7.

    Article  CAS  PubMed  Google Scholar 

  7. Vietri MT, D’elia G, Caliendo G, Resse M, Casamassimi A, Passariello L, et al. Hereditary prostate cancer: genes related, target therapy and prevention. Int J Mol Sci. 2021;22; https://doi.org/10.3390/ijms22073753.

  8. Raghallaigh HN, Eeles R. Genetic predisposition to prostate cancer: an update. Fam Cancer. 2021. https://doi.org/10.1007/S10689-021-00227-3

    Article  Google Scholar 

  9. Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl J Med. 2012;366:141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin X, Qu L, Chen Z, Xu C, Ye D, Shao Q, et al. A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. Prostate. 2013;73:169–75.

    Article  CAS  PubMed  Google Scholar 

  11. Maia S, Cardoso M, Pinto P, Pinheiro M, Santos C, Peixoto A, et al. Identification of two novel HOXB13 germline mutations in Portuguese prostate cancer patients. PLoS ONE. 2015;10:e0132728.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Grindedal EM, Møller P, Eeles R, Stormorken AT, Bowitz-Lothe IM, Landrø SM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomark Prev. 2009;18:2460–7.

    Article  CAS  Google Scholar 

  13. Castro E, Eeles R. The role of BRCA1 and BRCA2 in prostate cancer. Asian J Androl. 2012;14:409–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maia S, Cardoso M, Paulo P, Pinheiro M, Pinto P, Santos C, et al. The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer. Fam Cancer. 2016;15:111–21.

    Article  CAS  PubMed  Google Scholar 

  15. Paulo P, Maia S, Pinto C, Pinto P, Monteiro A, Peixoto A, et al. Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer. PLoS Genet. 2018;14; https://doi.org/10.1371/journal.pgen.1007355.

  16. Pritchard CC, Mateo J, Walsh MF, de Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl J Med. 2016;375:443–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Southey MC, Goldgar DE, 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. 2016;53:800.

    Article  CAS  PubMed  Google Scholar 

  18. Leongamornlert D, Saunders E, 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. 2019;76:329–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peixoto A, Santos C, Pinheiro M, Pinto P, Soares MJ, Rocha P, et al. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation. Breast Cancer Res Treat. 2011;127:671–9.

    Article  CAS  PubMed  Google Scholar 

  20. Peixoto A, Santos C, Pinto P, Pinheiro M, Rocha P, Pinto C, et al. The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry. Clin Genet. 2015;88:41–48.

    Article  CAS  PubMed  Google Scholar 

  21. Pinheiro M, Pinto C, Peixoto A, Veiga I, Mesquita B, Henrique R, et al. The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families. Clin Genet. 2013;84:244–50.

    Article  CAS  PubMed  Google Scholar 

  22. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. 2013; http://github.com/lh3/bwa (Accessed 28 Jul 2021).

  24. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. 2012; https://arxiv.org/abs/1207.3907v2 (Accessed 28 Jul 2021).

  25. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DePristo MA, Banks E, Poplin RE, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wei Z, Wang W, Hu P, Lyon GJ, Hakonarson H. SNVer: a statistical tool for variant calling in analysis of pooled or individual next-generation sequencing data. Nucleic Acids Res. 2011;39; https://doi.org/10.1093/NAR/GKR599.

  29. Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, Mardis ER, et al. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics. 2009;25:2283–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang K, Li M, Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38; https://doi.org/10.1093/NAR/GKQ603.

  31. Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100:267–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinforma. 2012;13:134.

    Article  CAS  Google Scholar 

  33. Browning SR, Browning BL. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet. 2007;81:1084–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Browning BL, Browning SR. Improving the accuracy and efficiency of identity-by-descent detection in population data. Genetics. 2013;194:459–71.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bandelt HJ, Forster P, Röhl A. Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evolution. 1999;16:37–48.

    Article  CAS  Google Scholar 

  36. Leigh JW, Bryant D. POPART: full-feature software for haplotype network construction. Methods Ecol Evolution. 2015;6:1110–6.

    Article  Google Scholar 

  37. Brandão A, Paulo P, Maia S, Pinheiro M, Peixoto A, Cardoso M, et al. The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor. Cancers. 2020;12:1–17.

    Article  Google Scholar 

  38. Abramowicz A, Gos M. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018;59:253–68.

    Article  Google Scholar 

  39. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.

    Article  CAS  PubMed  Google Scholar 

  40. Desmet FO, Hamroun D, Lalande M, Collod-Bëroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37; https://doi.org/10.1093/nar/gkp215.

  41. Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol. 2004;11:377–94.

    Article  CAS  PubMed  Google Scholar 

  42. Salameh A, Lee AK, Cardó-Vila M, Nunes DN, Efstathiou E, Staquicini FI, et al. PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proc Natl Acad Sci USA. 2015;112:1–6.

    Article  Google Scholar 

  43. Machida T, Fujita T, Ooo M, Ohira M, Isogai E, Mihara M, et al. Increased expression of proapoptotic BMCC1, a novel gene with the BNIP2 and Cdc42GAP homology (BCH) domain, is associated with favorable prognosis in human neuroblastomas. Oncogene. 2006;25:1931–42.

    Article  CAS  PubMed  Google Scholar 

  44. Clarke RA, Zhao Z, Guo A-Y, Roper K, Teng L, Fang Z-M, et al. New genomic structure for prostate cancer specific gene PCA3 within BMCC1: implications for prostate cancer detection and progression. PLoS ONE 2009;4:e4995.

  45. Yu W, McPherson JR, Stevenson M, van Eijk R, Heng HL, Newey P, et al. Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J Clin Endocrinol Metab. 2015;100:E360–E364.

    Article  CAS  PubMed  Google Scholar 

  46. Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, et al. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res. 2015;75:3720–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alsadoun N, MacGrogan G, Truntzer C, Lacroix-Triki M, Bedgedjian I, Koeb MH, et al. Solid papillary carcinoma with reverse polarity of the breast harbors specific morphologic, immunohistochemical and molecular profile in comparison with other benign or malignant papillary lesions of the breast: a comparative study of 9 additional cases. Mod Pathol. 2018;31:1367–80.

    Article  CAS  PubMed  Google Scholar 

  48. Pinto P, Peixoto A, Santos C, Rocha P, Pinto C, Pinheiro M, et al. Analysis of founder mutations in rare tumors associated with hereditary breast/ovarian cancer reveals a novel association of BRCA2 mutations with ampulla of vater carcinomas. PLoS ONE. 2016;11:e0161438.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Laitinen VH, Wahlfors T, Saaristo L, Rantapero T, Pelttari LM, Kilpivaara O, et al. HOXB13 G84E mutation in Finland: population-based analysis of prostate, breast, and colorectal cancer risk. Cancer Epidemiol Biomark Prev. 2013;22:452–60.

    Article  CAS  Google Scholar 

  50. Varon R, Seemanova E, Chrzanowska K, Hnateyko O, Piekutowska-Abramczuk D, Krajewska-Walasek M, et al. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet. 2000;8:900–2.

    Article  CAS  PubMed  Google Scholar 

  51. Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol. 2014;66:489–99.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dingerdissen HM, Torcivia-Rodriguez J, Hu Y, Chang TC, Mazumder R, Kahsay R. BioMuta and BioXpress: mutation and expression knowledgebases for cancer biomarker discovery. Nucleic Acids Res. 2018;46:D1128–36.

    Article  CAS  PubMed  Google Scholar 

  55. Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, et al. Pfam: the protein families database in 2021. Nucleic Acids Res. 2021;49:D412–9.

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Cancer Genetics Group, IPO Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal

    Marta Cardoso, Sofia Maia, Andreia Brandão, Paula Paulo & Manuel R. Teixeira

  2. Genome Center, University of California at Davis, Davis, CA, USA

    Ruta Sahasrabudhe, Paul Lott, Natalia Belter & Luis G. Carvajal-Carmona

  3. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA, USA

    Luis G. Carvajal-Carmona

  4. University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Luis G. Carvajal-Carmona

  5. Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal

    Manuel R. Teixeira

  6. School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal

    Manuel R. Teixeira

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  1. Marta Cardoso
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Contributions

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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Correspondence to Manuel R. Teixeira.

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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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