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Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2–ERG fusions



Men with early-onset prostate cancer are at increased risk for cancer-related mortality, yet the prevalence and spectrum of molecular alterations in this patient population is unknown. Here, we analyze comprehensive genomic profiling data to characterize the molecular drivers of early-onset prostate cancer in patients with clinically advanced and metastatic disease.


Next-generation sequencing was ordered as a part of routine clinical care for 10,189 patients with prostate cancer between 02/2013 and 03/2020 using commercially available comprehensive genomic profiling.


Deidentified genomic data for 10,189 unique patients with prostate cancer were obtained (median age = 66 y, range = 34–90 y). 439 patients were ≤50 y (4.3%), 1928 patients were between ages of 51 and 59 y (18.9%), and 7822 patients were ≥60 y  (76.8%). Of metastatic biopsy sites, lymph node, liver, and bone were the most common in all groups, accounting for 60.2% of all specimens. Overall, 97.4% of patients harbored pathologic genomic alterations. The most commonly altered genes were TP53, TMPRSS2–ERG, PTEN, AR, MYC, MLL2, RAD21, BRCA2, APC, SPOP, PIK3CA, RB1, MLL3, CDK12, ATM, and CTNNB1. Patients ≤50 y harbored significantly more TMPRSS2–ERG fusions than patients ≥60 y, while AR copy number alterations as well as SPOP and ASXL1 mutations were significantly less frequent.


Clinically advanced and metastatic early-onset prostate cancer is a distinct clinical subgroup with characteristic genomic alterations including increased frequency of TMPRSS2–ERG fusions and fewer AR, SPOP, and ASXL1 alterations.

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Fig. 1: Clinical characteristics of 10,189 men with prostate cancer.
Fig. 2: Trends in patient age for patients harboring a known oncogenic alterations.
Fig. 3: Frequency of known oncogenic alterations in patients with early- and typical-onset prostate cancer.
Fig. 4: Pathway alterations in early-onset prostate cancer.
Fig. 5: Age-related variation of MSI and TMB status.

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Code availability

Scripts used to analyze and present the data in this paper are available upon request (Python 2.7.16).


  1. Henley SJ, Ward EM, Scott S, Ma J, Anderson RN, Firth AU, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2020;126:2225–49.

    Article  Google Scholar 

  2. Etzioni R, Tsodikov A, Mariotto A, Szabo A, Falcon S, Wegelin J, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control. 2008;19:175–81.

    Article  Google Scholar 

  3. Collin SM, Martin RM, Metcalfe C, Gunnell D, Albertsen PC, Neal D, et al. Prostate-cancer mortality in the USA and UK in 1975–2004: an ecological study. Lancet Oncol. 2008;9:445–52.

    Article  Google Scholar 

  4. Salinas CA, Tsodikov A, Ishak-Howard M, Cooney KA. Prostate cancer in young men: an important clinical entity. Nat Rev Urol. 2014;11:317–23.

    Article  CAS  Google Scholar 

  5. Hu JC, Nguyen P, Mao J, Halpern J, Shoag J, Wright JD, et al. Increase in prostate cancer distant metastases at diagnosis in the United States. JAMA Oncol. 2017;3:705–7.

    Article  Google Scholar 

  6. Lin DW, Porter M, Montgomery B. Treatment and survival outcomes in young men diagnosed with prostate cancer: a population-based cohort study. Cancer. 2009;115:2863–71.

    Article  Google Scholar 

  7. Lange EM, Salinas CA, Zuhlke KA, Ray AM, Wang Y, Lu Y, et al. Early onset prostate cancer has a significant genetic component. Prostate. 2012;72:147–56.

    Article  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Hussain M, Daignault-Newton S, Twardowski PW, Albany C, Stein MN, Kunju LP, et al. Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer: results from NCI 9012. J Clin Oncol. 2017;36:991–9.

    Article  Google Scholar 

  10. Thorstenson A, Garmo H, Adolfsson J, Bratt O. Cancer specific mortality in men diagnosed with prostate cancer before age 50 years: a nationwide population based study. J Urol. 2017;197:61–6.

    Article  Google Scholar 

  11. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotech. 2013;31:1023–31.

    Article  CAS  Google Scholar 

  12. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34.

    Article  Google Scholar 

  13. Trabucco SE, Gowen K, Maund SL, Sanford E, Fabrizio DA, Hall MJ, et al. A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability–high cases in 67,000 patient samples. J Mol Diagn. 2019;21:1053–66.

    Article  CAS  Google Scholar 

  14. Koga Y, Song H, Chalmers ZR, Newberg J, Kim E, Carrot-Zhang J, et al. Genomic profiling of prostate cancers from men with African and European ancestry. Clin Cancer Res. 2020;26:4651–60.

    Article  CAS  Google Scholar 

  15. Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230–8.

    Article  CAS  Google Scholar 

  16. Abeshouse A, Ahn J, Akbani R, Ally A, Amin S, Andry CD, et al. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Article  CAS  Google Scholar 

  17. 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;26:2487–96.

    Article  CAS  Google Scholar 

  18. 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;382:2091–102.

    Article  Google Scholar 

  19. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16:2598–608.

    Article  CAS  Google Scholar 

  20. Maertens A, Tran VP, Maertens M, Kleensang A, Luechtefeld TH, Hartung T, et al. Functionally enigmatic genes in cancer: using TCGA data to map the limitations of annotations. Sci Rep. 2020;10:4106.

    Article  CAS  Google Scholar 

  21. Lallous N, Volik SV, Awrey S, Leblanc E, Tse R, Murillo J, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10.

    Article  Google Scholar 

  22. Henzler C, Li Y, Yang R, McBride T, Ho Y, Sprenger C, et al. Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun. 2016;7:13668.

    Article  CAS  Google Scholar 

  23. Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019;3:1–23.

    CAS  PubMed  Google Scholar 

  24. Li J, Xu C, Lee HJ, Ren S, Zi X, Zhang Z, et al. A genomic and epigenomic atlas of prostate cancer in Asian populations. Nature. 2020;580:93–9.

    Article  CAS  Google Scholar 

  25. Khani F, Mosquera JM, Park K, Blattner M, O’Reilly C, MacDonald TY, et al. Evidence for molecular differences in prostate cancer between African American and Caucasian men. Clin Cancer Res. 2014;20:4925–34.

  26. Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell. 2013;23:159–70.

    Article  CAS  Google Scholar 

  27. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470:214–20.

    Article  CAS  Google Scholar 

  28. Mosquera J-M, Mehra R, Regan MM, Perner S, Genega EM, Bueti G, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009;15:4706–11.

    Article  CAS  Google Scholar 

  29. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun X-W, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–8.

    Article  CAS  Google Scholar 

  30. Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera J-M, Setlur S, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66:8337–41.

    Article  CAS  Google Scholar 

  31. Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 2008;68:3584–90.

    Article  CAS  Google Scholar 

  32. Clark JP, Cooper CS. ETS gene fusions in prostate cancer. Nat Rev Urol. 2009;6:429–39.

    Article  CAS  Google Scholar 

  33. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol. 2011;29:3659–68.

    Article  CAS  Google Scholar 

  34. Demichelis F, Rubin MA. TMPRSS2-ETS fusion prostate cancer: biological and clinical implications. J Clin Pathol. 2007;60:1185–6.

    Article  Google Scholar 

  35. FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, et al. Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer. 2008;8:230.

    Article  Google Scholar 

  36. Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 2008;27:253–63.

    Article  CAS  Google Scholar 

  37. Weischenfeldt J, Korbel JO. Genomes of early onset prostate cancer. Curr Opin Urol. 2017;27:481–7.

    Article  Google Scholar 

  38. Bostwick DG, Burke HB, Djakiew D, Euling S, Ho S-m, Landolph J, et al. Human prostate cancer risk factors. Cancer. 2004;101:2371–490.

    Article  CAS  Google Scholar 

  39. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat J-P, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    Article  CAS  Google Scholar 

  40. Antonarakis ES, Isaacsson Velho P, Fu W, Wang H, Agarwal N, Santos VS, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, Poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis Oncol. 2020;4:370–81.

    Article  Google Scholar 

  41. Swami U, Velho PI, Nussenzveig R, Chipman J, Santos VS, Erickson S, et al. Association of SPOP mutations with outcomes in men with de novo metastatic castration-sensitive prostate cancer. Eur Urol. 2020;78:652–6.

  42. Boysen G, Rodrigues DN, Rescigno P, Seed G, Dolling D, Riisnaes R, et al. SPOP-mutated/CHD1-deleted lethal prostate cancer and abiraterone sensitivity. Clin Cancer Res. 2018;24:5585–93.

    Article  CAS  Google Scholar 

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This work was supported by grants from the National Cancer Institute: F30CA250248, P50CA180995, and by the Prostate Cancer Foundation: 2017CHAL2044.

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Correspondence to Maha H. A. Hussain or Sarki A. Abdulkadir.

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EME, GMF, and JSR are employees of Foundation Medicine, Inc. No other potential conflicts of interest were reported by the authors.

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Chalmers, Z.R., Burns, M.C., Ebot, E.M. et al. Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2–ERG fusions. Prostate Cancer Prostatic Dis 24, 558–566 (2021).

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