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.

  • Review Article
  • Basic Research
  • Published:

Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine

Prostate Cancer and Prostatic Diseases volume 26, pages 655–664 (2023)Cite this article

Subjects

Abstract

Background

The goal of precision medicine in prostate cancer (PCa) is to individualize the treatment according to the patient’s germline mutation status. PCa has a very high rate of genetic predisposition compared with other cancers in men, with an estimated rate of cancers ascribable to hereditary factors of 5–15%.

Methods

A systematic search (PubMed, Web of Science, and ClinicalTrials.gov) of English literature from 2000 to 2022, using the keywords “prostate cancer”, “germline mutations”, “family history”, and “inheritance” was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Results

The search identified 980 publications. Of these, 200 papers were removed before screening (duplicates, non-English literature, and publication year before 2000) and 245 records were excluded after title/abstract screening. Finally, 50 articles were included in the final analysis. We analyze the latest evidence on the genetic basis of PCa predisposition and clinical implications for more personalized screening protocols and therapeutic management of this high-prevalent cancer.

Discussion

Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa. Germline testing and genetic counseling have increasingly important implications in cancer screening and therapeutic decisions making for patients affected by PCa. Patients with localized PCa and some gene mutations are more likely to develop aggressive cancer, so active treatment may be preferable to active surveillance for these patients. Moreover, in patients with metastatic PCa, these gene alterations may be useful biomarkers for predicting response to specific therapy such as PARP inhibitors, recently approved for the treatment of metastatic castration-resistant PCa. The evidence supports recent guidelines and recommendations considering germline genetic testing for patients with a positive family history of PCa or men with high risk or metastatic disease.

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: Flowchart.
Fig. 2: PCa susceptibility model.

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. Ca Cancer J Clin. 2021;71:7–33. https://doi.org/10.3322/caac.21654

    Article  PubMed  Google Scholar 

  2. Bostwick DG, Burke HB, Djakiew D, Euling S, Ho S, Landolph J, et al. Human prostate cancer risk factors. Cancer. 2004;101:2371–2490. https://doi.org/10.1002/cncr.20408

    Article  CAS  PubMed  Google Scholar 

  3. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019;10(Apr):63–89. https://doi.org/10.14740/wjon1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hsing AW, Sakoda LC, Chua S. Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr. 2007;86:s843–857. https://doi.org/10.1093/ajcn/86.3.843s

    Article  PubMed  Google Scholar 

  5. Bruner DW, Moore D, Parlanti A, Dorgan J, Engstorm P. Relative risk of prostate cancer for men with affected relatives: systematic review and meta- analysis. Int J Cancer. 2003;107:797–803. https://doi.org/10.1002/ijc.11466

    Article  CAS  PubMed  Google Scholar 

  6. Kiciński M, Vangronsveld J, Nawrot TS. An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One. 2011;6:e27130 https://doi.org/10.1371/journal.pone.0027130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sacco E, Prayer-Galetti T, Pinto F, Ciaccia M, Fracalanza S, Betto G, et al. Familial and hereditary prostate cancer by definition in an Italian surgical series: clinical features and outcome. Eur Urol. 2005;47:761–768. https://doi.org/10.1016/j.eururo.2005.01.016

    Article  PubMed  Google Scholar 

  8. Mikropoulos C, Goh C, Leongamornlert D, Kote-Jarai Z, Eeles R. Translating genetic risk factors for prostate cancer to clinic: 2013 and beyond. Future Oncol. 2014;10:1679–1694. https://doi.org/10.2217/fon.14.72

    Article  CAS  PubMed  Google Scholar 

  9. Dias A, Kote-Jarai Z, Mikropoulos C, Eeles R. Prostate Cancer Germline Variations and Implications for Screening and Treatment. Cold Spring Harb Perspect Med. 2018;8:a030379 https://doi.org/10.1101/cshperspect.a030379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schumacher FR, Olama AAA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet. 2018;50:928–936. https://doi.org/10.1038/s41588-018-0142-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs WB, et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol. 1993;150:797–802. https://doi.org/10.1016/s002-5347(17)35617-3

    Article  CAS  PubMed  Google Scholar 

  12. Rebbeck TR. Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography. Semin Radiat Oncol. 2017;27:3–10. https://doi.org/10.1016/j.semradonc.2016.08.002

    Article  PubMed  Google Scholar 

  13. Madersbacher S, Alcaraz A, Emberton M, Hammerer P, Ponholzer A, Schroder FH, et al. The influence of family history on prostate cancer risk: implications for clinical management. BJU Int. 2011;107:716–721. https://doi.org/10.1111/j.1464-410X.2010.10024.x

    Article  PubMed  Google Scholar 

  14. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71 https://doi.org/10.1136/bmj.n71

    Article  PubMed  PubMed Central  Google Scholar 

  15. Barber L, Gerke T, Markt SC, Peisch SF, Wilson KM, Ahearn T, et al. Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clin Cancer Res. 2018;24:5910–5917. https://doi.org/10.1158/1078-0432.CCR-18-0370

    Article  PubMed  PubMed Central  Google Scholar 

  16. Haraldsdottir S, Hampel H, Wei L, Wu C, Frankel W, Bekaii-Saab T, et al. Prostate cancer incidence in males with Lynch syndrome. Genet Med. 2014;16:553–557. https://doi.org/10.1038/gim.2013.193

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kote-Jarai Z, Easton DF, Stanford JL, Ostrander EA, Schleutker J, Ingles SA, et al. Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium. Cancer Epidemiol Biomark Prev. 2008;17:2052–2061. https://doi.org/10.1158/1055-9965.EPI-08-0317

    Article  CAS  Google Scholar 

  18. Eeles RA, Olama AAA, Benlloch S, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet. 2013;45:385–391. https://doi.org/10.1038/ng.2560. 391e1-2

    Article  CAS  PubMed  Google Scholar 

  19. Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet. 2021;53:65–75. https://doi.org/10.1038/s41588-020-00748-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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;22:3753 https://doi.org/10.3390/ijms22073753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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;375:443–453. https://doi.org/10.1056/nejmoa1603144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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. 2014;110:1663–1672. https://doi.org/10.1038/bjc.2014.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee YC, Lee YL, Li CY. BRCA Genes and Related Cancers: A Meta-Analysis from Epidemiological Cohort Studies. Med (Kaunas). 2021;57:905 https://doi.org/10.3390/medicina57090905

    Article  Google Scholar 

  24. Silvestri V, Lesli G, Barnes DR, Agnarsson BA, Aittomaki K, Alducci E, et al. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2(CIMBA). JAMA Once. 2020;6:1–13. https://doi.org/10.1001/jamaoncol.2020.2134

    Article  Google Scholar 

  25. Leongamornlert D, Mahmud N, Tymrakiewicz M, Saunders E, Dadaev T, Castro E, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012;106:1697–1701. https://doi.org/10.1038/bjc.2012.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: Implications for genetic testing in prostate cancer patients. Br J Cancer. 105:1230–1234. https://doi.org/10.1038/bjc.2011.383.

  27. Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16:2115–2121. https://doi.org/10.1158/1078-0432.CCR-09-2871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maier C, Herkommer K, Luedeke M, Rinckleb A, Schrader M, Vogel W. Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations. Prostate. 2014;74:1444–1451. https://doi.org/10.1002/pros.22860

    Article  CAS  PubMed  Google Scholar 

  29. Castro E, Romero-Laorden N, Del Pozo A, Lozano R, Medina A, Puente J, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2019;37:490–503. https://doi.org/10.1200/JCO.18.00358

    Article  CAS  PubMed  Google Scholar 

  30. Lang SH, Swift SL, White H, Misso K, Kleijnen J, Quek RGW. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol. 2019;55:597–616. https://doi.org/10.3892/ijo.2019.4842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Na R, Zheng SL, Han M, Yu H, Jiang H, Jiang D, 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. 2017;71:740–747. https://doi.org/10.1016/j.eururo.2016.11.033

    Article  CAS  PubMed  Google Scholar 

  32. Carter HB, Helfand B, Mamawala M, Wu Y, Landis P, Yu H, et al. Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur Urol. 2019;75:743–749. https://doi.org/10.1016/j.eururo.2018.09.021

    Article  CAS  PubMed  Google Scholar 

  33. Angele S, Falconer A, Edwards SM, Dork T, Bremer M, Moullan N, et al. ATM polymorphisms as risk factors for prostate cancer development. Br J Cancer. 2004;91:783–787. https://doi.org/10.1038/sj.bjc.6602007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang Y, Dai B, Ye D. CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med. 2015;8:15708–15715.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Naslund-Koch C, Nordestgaard BG, Bojesen SE. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2∗1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016;34:1208–1216. https://doi.org/10.1200/JCO.2015.63.3594

    Article  CAS  PubMed  Google Scholar 

  36. Cybulski C, Wokolorczyk D, Kluzniak W, Jakubowska A, Gorski B, Gronwald J, et al. An inherited NBN mutations is associated with poor prognosis prostate cancer. Br J Cancer. 2013;108:461–468. https://doi.org/10.1038/bjc.2012.486

    Article  CAS  PubMed  Google Scholar 

  37. Wu Y, Yu H, Zheng SL, Na R, Mamawala M, Landis T, et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate 2018;78:607–615. https://doi.org/10.1002/pros.23505

    Article  CAS  PubMed  Google Scholar 

  38. Southey MC, Teo ZL, Winship I. PALB2 and breast cancer: ready for clinical translation! Apple Clin Genet. 2013;6:43–52. https://doi.org/10.2147/TACG.S34116

    Article  CAS  Google Scholar 

  39. Nicolosi P, Ledet E, Yang S, Michakski S, Freschi B, O’Leary E, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol. 2019;5:523–528. https://doi.org/10.1001/jamaoncol.2018.6760

    Article  PubMed  PubMed Central  Google Scholar 

  40. Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DYH, et al. Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat. 2012;33:95–99. https://doi.org/10.1002/humu.21625

    Article  CAS  PubMed  Google Scholar 

  41. Norris JD, Chang CY, Wittmann BM, Kunder RS, Cui H, Fan D, et al. The Homeodomain Protein HOXB13 Regulates the Cellular Response to Androgens. Mol Cell. 2019;36:405–416. https://doi.org/10.1016/j.molcel.2009.10.020

    Article  CAS  Google Scholar 

  42. Cai Q, Wang X, Li X, Gong R, Guo X, Tang Y, et al. Germline HOXB13 p. Gly84Glu mutation and cancer susceptibility: A pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015;6:42312–42321. https://doi.org/10.18632/oncotarget.5994

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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;366:141–149. https://doi.org/10.1056/NEJMoa1110000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Baretti M, Le DT. DNA mismatch repair in cancer. Pharm Ther. 2018;189:45–62. https://doi.org/10.1016/j.pharmthera.2018.04.004

    Article  CAS  Google Scholar 

  45. Ponti G, Castellsagué E, Ruini C, Percesepe A, Tomasi A. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet. 2015;87:507–516. https://doi.org/10.1111/cge.12529.

    Article  CAS  PubMed  Google Scholar 

  46. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in lynch syndrome: A systematic review and meta-Analysis. Cancer Epidemiol Biomark Prev. 2014;23:437–449. https://doi.org/10.1158/1055-9965.EPI-13-1165

    Article  CAS  Google Scholar 

  47. Wu Y, Yu H, Li S, Wiley K, Zheng SL, 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. 2020;3:224–230. https://doi.org/10.1016/j.euo.2019.12.003

    Article  PubMed  Google Scholar 

  48. Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, et al. MSH2 Loss in Primary Prostate Cancer. Clin Cancer Res. 2017;23:6863–6874. https://doi.org/10.1158/1078-0432.CCR-17-0955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schaid DJ, McDonnel SK, FitzGerald LM, DeRycke L, Fogarty Z, Giles GG, et al. Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. Eur Urol. 2021;79:353–361. https://doi.org/10.1016/j.eururo.2020.07.038

    Article  CAS  PubMed  Google Scholar 

  50. Nguyen-Dumont T, Dowty JG, Maclnnis RJ, Steen JA, Riaz M, Dugué PA, et al. Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer. Cancers. 2021;13:1945 https://doi.org/10.3390/cancers13071495

    Article  CAS  Google Scholar 

  51. Giri VN, Knudsen KE, Kelly WK, Abida W, Andriole GL, Bangma CH, et al. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol. 2018;36:414–424. https://doi.org/10.1200/JCO.2017.74.1173

    Article  CAS  PubMed  Google Scholar 

  52. Doan DK, Schmidt KT, Chau CH, Figg WD, et al. Germline Genetics of Prostate Cancer: Prevalence of Risk Variants and Clinical Implications for Disease Management. Cancers. 2021;13:2154 https://doi.org/10.3390/cancers13092154

    Article  PubMed  PubMed Central  Google Scholar 

  53. Allemailem KS, Almatroudi A, Alrumaihi F, Almansour NM, Aldakheel FM, Rather RA, et al. Single nucleotide polymorphisms (SNPs) in prostate cancer: its implications in diagnostics and therapeutics. Am J Transl Res. 2021;13:3868–3889.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Macinnis RJ, Antoniou AC, Eeles RA, Severi G, Olama AAA, McGuffog L, et al. A risk prediction algorithm based on family history and common genetic variants: application to prostate cancer with potential clinical impact. Genet Epidemiol. 2011;35:549–556. https://doi.org/10.1002/gepi.20605

    Article  PubMed  PubMed Central  Google Scholar 

  55. Gronberg H, Adolfsson J, Aly M, Nordstrom T, Wiklund P, Brandberg Y, et al. Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol. 2015;16:1667–1676. https://doi.org/10.1016/S1470-2045(15)00361-7

    Article  PubMed  Google Scholar 

  56. Castro E, Mikropoulos C, Bancroft EK, Dadaev T, Goh C, Taylor N, et al. The PROFILE Feasibility Study: Targeted Screening of Men With a Family History of Prostate Cancer. Oncologist 2016;21:716–722. https://doi.org/10.1634/theoncologist.2015-0336

    Article  PubMed  PubMed Central  Google Scholar 

  57. Eeles RA. The PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment. https://www.clinicaltrials.gov/ct2/show/NCT02543905?term=nct02543905&draw=2&rank=1

  58. R. A. Eeles, Institute of Cancer Research and Royal Marsden Hospital. “The IMPACT Study - Identification of Men With a Genetic Predisposition to Prostate Cancer. NCT00261456

  59. Bancroft EK, Page EC, Brook MN, Thomas S, Taylor N, Pope J, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initiali results from an international prospective study. Lancet Oncol. 2021;22:1618–1631. https://doi.org/10.1016/S1470-2045(21)00522-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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;66:489–499. 10.106/j.eururo.2014.01.003

    Article  PubMed  PubMed Central  Google Scholar 

  61. National Comprehensive Cancer Network Guidelines Version 2.2021. Available online: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (accessed on February 2022).

  62. European Association of Urology. Prostate Cancer guidelines. Available online: https://uroweb.org/guidelines/prostate-cancer (accessed on February 2022).

  63. Parker C, Castro E, Fizazi K, Heindenreich A, Ost P, Procopio G et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Available: https://www.annalsofoncology.org/action/showPdf?pii=S0923-7534%2820%2939898-7

  64. Chen RC, Rumble BR, Loblaw DA, Finelli A, Ehdaie B, Cooperberg MR, et al. Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016;34:2182–2190. https://doi.org/10.1200/JCO.2015.65.7759

    Article  PubMed  Google Scholar 

  65. Telang JM, Lane BR, Cher ML, Miller DC, Dupree JM. Prostate cancer family history and eligibility for active surveillance: a systematic review of the literature. BJU Int. 2017;120:464–467. https://doi.org/10.1111/bju.13862

    Article  PubMed  Google Scholar 

  66. Halstuch D, Ber Y, Kedar D, Golan S, Baniel J, Margel D. Short-term outcomes of active surveillance for low risk prostate cancer among men with germline DNA repair gene mutations. J Urol. 2020;204:707–713. https://doi.org/10.1097/ju.0000000000001027

    Article  PubMed  Google Scholar 

  67. De Bono J. TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer. https://clinicaltrials.gov/ct2/show/NCT01682772

  68. Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP - B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:162–174. https://doi.org/10.1016/S1470-2045(19)30684-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. De Bono J, Hussain M. Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study) https://clinicaltrials.gov/ct2/show/NCT02987543

  70. A Study of Rucaparib in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2). https://clinicaltrials.gov/ct2/show/NCT02952534

  71. An Efficacy and Safety Study of Niraparib in Men With Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies (Galahad). https://clinicaltrials.gov/ct2/show/NCT02854436

  72. De Bono J. A Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer. https://clinicaltrials.gov/ct2/show/NCT03148795?term=NCT03148795&draw=2&rank=1

  73. 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;373:1697–1708. https://doi.org/10.1056/NEJMoa1506859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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. 2020;382:2091–2102. https://doi.org/10.1056/NEJMoa1911440

    Article  PubMed  Google Scholar 

  75. Adiba W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, et al. Rucaparib in Men With Metastatic Castration Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. 2020;38:3763–3772. https://doi.org/10.1200/JCO.20.01035

    Article  Google Scholar 

  76. Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis from the Phase II TRITON2 Study. Clin Cancer Res. 2020;26:2487–2496. https://doi.org/10.1158/1078-0432.CCR-20-0394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Smith MR, Scher HI, Sandhu S, Efstathiou E, Lara PN Jr. Yu EY, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD); a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022;23:362–373. https://doi.org/10.1016/S1470-2045(21)00757-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. De Bono JS, Mehra N, Scagliotti GV, Castro E, Dorff T, Stirling A, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Once. 2021;22:1250–1264. https://doi.org/10.1016/S1470-2045(21)00376-4

    Article  Google Scholar 

  79. Le DT, Durham JN, Smith KN, Wang H, Barlett BR, Aulakh LK, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. https://doi.org/10.1126/science.aan6733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Antonarakis ES, Shaukat F, Velho PI, Kaur H, Shenderov E, Pardoll DM, et al. Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations. Eur Urol. 2019;75:378–382. https://doi.org/10.1016/j.eururo.2018.10.009

    Article  CAS  PubMed  Google Scholar 

  81. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Once. 2019;5:471–478. https://doi.org/10.1001/jamaoncol.2018.5801

    Article  Google Scholar 

  82. Barata P, Agarwal N, Nussenzveig R, Gerendash B, Jaeger E, Hatton W, et al. Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA. J Immunother Cancer. 2020;8:e001065. https://doi.org/10.1136/jitc-2020-001065

    Article  PubMed  PubMed Central  Google Scholar 

  83. Mota JM, Barnett E, Nauseef JT, Nguyen B, Stopsack KH, Wibmer A, et al. Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations. JCO Precis Oncol. 2020;4:355–366. https://doi.org/10.1200/po.19.00346

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Urology Department, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Filippo Marino, Angelo Totaro, Carlo Gandi, Riccardo Bientinesi, Stefano Moretto, Filippo Gavi, PierFrancesco Bassi & Emilio Sacco

  2. Anatomic Pathology and Histology Department, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Francesco Pierconti

  3. Medical Oncology Department, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Roberto Iacovelli

Authors
  1. Filippo Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angelo Totaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Gandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Riccardo Bientinesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefano Moretto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Filippo Gavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesco Pierconti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roberto Iacovelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. PierFrancesco Bassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Emilio Sacco
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design FM, ES; Acquisition of data FM, AT, CG, RB; Writing-original draft preparation FM, ES; Writing-review and editing AT, CG, RB, SM, FG; Critical revision of the paper for important intellectual content: RI, FP, PB, ES. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Filippo Marino.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marino, F., Totaro, A., Gandi, C. et al. Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine. Prostate Cancer Prostatic Dis 26, 655–664 (2023). https://doi.org/10.1038/s41391-022-00609-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-022-00609-3

This article is cited by

Search

Advanced search

Quick links