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Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

Abstract

Background

DNA repair gene mutations are present in 8–10% of localized prostate cancers. It is unknown whether this is influenced by clinicopathologic factors.

Methods

We interrogated localized prostate adenocarcinomas with tumor DNA sequencing information from the TCGA validated (n = 333) and Nature Genetics (n = 377) datasets. Homologous recombination repair genes included in our analysis were: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T, pathologic T, and pathologic N stage. Odds ratios and Fisher’s exact tests were used to compare proportions between categories.

Results

Patients with Gleason grade groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI: 1.2–4.2; 10.3% versus 5.0%) and were 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.3–6.6; 7.0% versus 2.7%) compared to those in Gleason grade groups 1–2. Patients with pathologic T3 and T4 stage (pT3/pT4) were 2.6 times more likely to have any DNA repair mutation (95% CI: 1.3–6.6; 13.0% versus 5.5%) and were 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.2–11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason grade group ≥ 3 and clinical stage ≥ cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2.

Conclusions

The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason grade groups, with maximal enrichment observed in those with Gleason grade group ≥ 3 and clinical stage ≥ cT3 disease. This information can be used to guide eligibility criteria for genomically targeted clinical trials in the neoadjuvant/adjuvant settings.

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References

  1. 1.

    Prostate Cancer—Cancer Stat Facts. SEER Cancer Statistics. https://seer.cancer.gov/statfacts/html/prost.html. Accessed 5 Feb 2018.

  2. 2.

    Borque Á, Rubio-Briones J, Esteban LM, Sanz G, Domínguez-Escrig J, Ramírez-Backhaus M, et al. Implementing the use of nomograms by choosing threshold points in predictive models: 2012 updated Partin Tables vs a European predictive nomogram for organ-confined disease in prostate cancer. BJU Int. 2014;113:878–86.

    Article  Google Scholar 

  3. 3.

    Graefen M, Karakiewicz PI, Cagiannos I, Quinn DI, Henshall SM, Grygiel JJ, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2002;20:3206–12.

    Article  Google Scholar 

  4. 4.

    Makarov DV, Trock BJ, Humphreys EB, Mangold LA, Walsh PC, Epstein JI, et al. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology. 2007;69:1095–101.

    Article  Google Scholar 

  5. 5.

    Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017;541:359–64.

    CAS  Article  Google Scholar 

  6. 6.

    Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Article  Google Scholar 

  7. 7.

    Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    CAS  Article  Google Scholar 

  8. 8.

    Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68:186–93.

    CAS  Article  Google Scholar 

  9. 9.

    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.

    CAS  Article  Google Scholar 

  10. 10.

    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;110:1663–72.

    CAS  Article  Google Scholar 

  11. 11.

    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. 2011;105:1230–4.

    CAS  Article  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244–50.

    CAS  Article  Google Scholar 

  14. 14.

    Isaacsson Velho P, Silberstein JL, Markowski MC, Luo J, Lotan TL, Isaacs WB, et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018;78:401–7.

    CAS  Article  Google Scholar 

  15. 15.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  Google Scholar 

  16. 16.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  Google Scholar 

  17. 17.

    Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50:645–51.

    CAS  Article  Google Scholar 

  18. 18.

    Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40:244–52.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    American Joint Committee on Cancer. Prostrate. In: AJCC cancer staging manual. New York, NY: Springer, 2017, p. 715–25.

  20. 20.

    Teply BA, Antonarakis ES. Treatment strategies for DNA repair-deficient prostate cancer. Expert Rev Clin Pharmacol. 2017;10:889–98.

    CAS  Article  Google Scholar 

  21. 21.

    R Studio Team. R studio: integrated development for R. R Studio, Inc: Boston, MA; 2015. http://www.rstudio.com/.

  22. 22.

    Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, Jonasson JG, Olafsdóttir EJ, Olafsdóttir GH, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:929–35.

    Article  Google Scholar 

  23. 23.

    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. 2017;36:414–24.

    Article  Google Scholar 

  24. 24.

    National Comprehensive Cancer Network. Prostate cancer—NCCN evidence blocks. 2017. https://www.nccn.org/professionals/physician_gls/pdf/prostate_blocks.pdf. Accessed February 2018.

  25. 25.

    Antonarakis ES, Lu C, Luber B, Liang C, Wang H, Chen Y, et al. Germline DNA-repair gene mutations and outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide. Eur Urol. 2018; 74:218–25.

  26. 26.

    Pomerantz MM, Spisák S, Jia L, Cronin AM, Csabai I, Ledet E, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer. 2017;123:3532–9.

    CAS  Article  Google Scholar 

  27. 27.

    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    CAS  Article  Google Scholar 

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Acknowledgements

This work was partially supported by National Institutes of Health Grant P30 CA006973 (ESA) and Department of Defense grant W81XWH-16-PCRP-CCRSA (ESA).

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Correspondence to Emmanuel S. Antonarakis.

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Conflict of interest

Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Medivation, ESSA, AstraZeneca, Clovis and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and he is the co-inventor of a biomarker technology that has been licensed to Tokai and Qiagen. Catherine Handy Marshall received research support through the Conquer Cancer Foundation/Bristol Meyers Squibb. The remaining authors declare that they have no conflict of interest.

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Marshall, C.H., Fu, W., Wang, H. et al. Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis 22, 59–65 (2019). https://doi.org/10.1038/s41391-018-0086-1

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