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Genetic profiling of hormone-sensitive and castration-resistant prostate cancers and identification of genetic mutations prone to castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 26, pages 180–187 (2023)Cite this article

Subjects

Abstract

Background

Genetic profiling of patients with prostate cancer could potentially identify mutations prone to castration-resistant prostate cancer (CRPC). Here, we aimed to identify the differences in genetic profiles of patients with hormone-sensitive prostate cancer (HSPC) and CRPC and stratify HSPC patients to identify mutations associated with CRPC progression.

Methods

A total of 103 samples were collected, including 62 DNA samples from the tumor tissues of 59 HSPC patients and 41 cell-free DNA (cfDNA) samples from prostate cancer patients at different cancer stages. Targeted sequence was conducted on both the tissue DNA and cfDNA. The associations between mutations and clinical outcomes (CRPC-free time) were analyzed using χ2 test, logistic regression analysis, Kaplan–Meier analysis, and Cox regression analysis.

Results

By comparing to that of cfDNA sequencing, the results from DNA sequencing of 1-needle (80%) and mixed 12-needle (77.8%) biopsies are highly comparable. FOXA1 (30.5%), CDK12 (23.7%), and TP53 (22.0%) were the top 3 most frequently mutated genes in HSPC patients; 50.8% (30/59) and 44.1% (26/59) HSPC patients had mutations in DDR and HRR pathway, respectively. Mutations in AR and APC as well as the members involved in the regulation of stem cell pluripotency and EMT pathway were often observed in CRPC samples. We established a panel of four genetic mutations (MSH2, CDK12, TP53, and RB1) to predict the risk of CRPC early progression with concordance index = 0.609 and the area under curve of the ROC curve as 0.838.

Conclusions

In this study, we demonstrated that the cfDNA can be used in genetic profiling in prostate cancer and our newly established panel is capable of predicting which mHSPC patient has a high risk of early CRPC progression.

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Fig. 1: Comparison of genetic mutations using either cfDNA or tissue DNA samples.
Fig. 2: The genetic profile of 59 HSPC patients.
Fig. 3: The genetic profile in CRPC cfDNA samples.
Fig. 4: The flowchart of screening genetic mutations associated with CRPC-free time.
Fig. 5: Association between our newly identified panel and CRPC development as well as prognosis of prostate cancer.

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Data availability

The raw data in this study were freely available in Genome Sequence Archive (GSA) database with the project number PRJCA009634.

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Acknowledgements

The authors thank all patients in this study for their collaboration and the Geneplus (Beijing, China) for conducting the sequencing.

Funding

This work was supported by the National Natural Science FoundatiPRon of China (Grant Nos: 82172807 and 82172721) and University Research Project of Army Medical University (2017XYY07, 2018XLC1014, 2019CXLCB006 and 17BJZ13).

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Authors and Affiliations

  1. Department of Urology, Daping Hospital, Army Medical University, Chongqing, PR China

    Ze Wang, Xuzhi Yan, Peng Tang, Tang Tang, Yapeng Wang, Song Peng, Shuo Wang, Weihua Lan, Luofu Wang, Yao Zhang, Jun Zhang, Ke Li, Zehua Shu, Jing Xu, Jun Jiang & Qiuli Liu

  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, PR China

    Jun Qin

  3. Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

    Dianzheng Zhang

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Contributions

QL and JJ were responsible for designing the study, data interpretation, writing the manuscript, and approving the final version. ZW was responsible for the acquisition of data, data analysis, data interpretation, writing of the manuscript, and statistical analysis. XY contributed to the acquisition of data, data analysis, acquisition of data, and statistical analysis. PT conducted the acquisition of data and data analysis. JQ contributed to data interpretation. DZZ contributed to the manuscript writing. TT, YW, SP, SW, WL, LW, YZ, JZ, KL, ZS, and JX contributed to the acquisition of data.

Corresponding authors

Correspondence to Jun Jiang or Qiuli Liu.

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The authors declare no competing interests.

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This study was approved by the Committee for Ethics of Daping hospital (No. 2018_28). Informed consent was obtained from every patient enrolled in this study.

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Wang, Z., Yan, X., Tang, P. et al. Genetic profiling of hormone-sensitive and castration-resistant prostate cancers and identification of genetic mutations prone to castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 26, 180–187 (2023). https://doi.org/10.1038/s41391-022-00618-2

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