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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

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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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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