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Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer

Prostate Cancer and Prostatic Diseases volume 23, pages 316–323 (2020)Cite this article

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Abstract

Introduction

Germline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.

Methods

Germline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.

Results

A comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.

Conclusions

This study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.

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Acknowledgements

RA, NS, ES, and SGZ are supported by the Prostate Cancer Foundation. This work was supported in part with support from the National Cancer Institute (R01CA172382 and R01CA190289 to NS). Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812 to EJS). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C.

Author information

Author notes

  1. These authors contributed equally: William S. Chen, Eric Feng

  2. These authors jointly supervised: Eric J. Small, Nima Sharifi, Shuang G. Zhao

Authors and Affiliations

  1. Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

    William S. Chen, Eric L. Feng, Adam Foye & Shuang G. Zhao

  2. Yale School of Medicine, New Haven, CT, USA

    William S. Chen

  3. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    William S. Chen, Eric L. Feng, Rahul Aggarwal, Adam Foye, Eric J. Small & Shuang G. Zhao

  4. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Rahul Aggarwal, Adam Foye & Eric J. Small

  5. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Tomasz M. Beer

  6. Rogel Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Joshi J. Alumkal

  7. University of British Columbia, Vancouver, British Columbia, Canada

    Martin Gleave & Kim N. Chi

  8. University of California Los Angeles, Los Angeles, CA, USA

    Robert E. Reiter & Matthew B. Rettig

  9. VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Matthew B. Rettig

  10. Department of Urologic Surgery, University of California, Davis, Sacramento, CA, USA

    Christopher P. Evans

  11. Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Nima Sharifi

  12. Department of Urology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

    Nima Sharifi

  13. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Nima Sharifi

  14. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Shuang G. Zhao

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Correspondence to Shuang G. Zhao.

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Conflict of interest

SGZ has patents filed unrelated to this work with Decipher Biosciences and Celgene. A patent for 3β-hydroxysteroid dehydrogenase in steroid-dependent disease has been filed by Cleveland Clinic. JJA has performed consulting or held an advisory role with Astellas Pharma, Bayer, Merck, and Janssen Biotech, Inc. KNC has received grant support and honoraria from Astellas Pharma, Janssen, Sanofi, AstraZeneca, Bayer, Essa Pharma, Pfizer, and Roche. The remaining authors declare that they have no conflict of interest.

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Chen, W.S., Feng, E.L., Aggarwal, R. et al. Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer. Prostate Cancer Prostatic Dis 23, 316–323 (2020). https://doi.org/10.1038/s41391-019-0188-4

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