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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

Prostate Cancer and Prostatic Diseases volume 24, pages 558–566 (2021)Cite this article

Subjects

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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).

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Funding

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

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Author notes

  1. These authors contributed equally: Zachary R. Chalmers, Michael C. Burns

  2. These authors jointly supervised this work: Maha H. A. Hussain, Sarki A. Abdulkadir

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Zachary R. Chalmers, Michael C. Burns, Maha H. A. Hussain & Sarki A. Abdulkadir

  2. Foundation Medicine, Inc, Cambridge, MA, USA

    Ericka M. Ebot, Garrett M. Frampton & Jeffrey S. Ross

  3. Upstate Medical University, Syracuse, NY, USA

    Jeffrey S. Ross

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  1. Zachary R. Chalmers
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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). https://doi.org/10.1038/s41391-020-00314-z

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