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

William S. Chen, Eric L. Feng, Rahul Aggarwal, Adam Foye, Tomasz M. Beer, Joshi J. Alumkal, Martin Gleave, Kim N. Chi, Robert E. Reiter, Matthew B. Rettig, Christopher P. Evans, Eric J. Small, Nima Sharifi, Shuang G. Zhao

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    JournalProstate Cancer and Prostatic Diseases
    DOIs
    StateAccepted/In press - Jan 1 2019

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    Androgens
    Prostatic Neoplasms
    Survival
    Neoplasms
    Genes
    Castration
    Genome
    RNA Sequence Analysis
    Therapeutics
    cdc Genes
    Survival Analysis
    Transcriptome
    Alleles
    Cell Proliferation
    Neoplasm Metastasis
    Biopsy
    DNA

    ASJC Scopus subject areas

    • Oncology
    • Urology
    • Cancer Research

    Cite this

    Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer. / Chen, William S.; Feng, Eric L.; Aggarwal, Rahul; Foye, Adam; Beer, Tomasz M.; Alumkal, Joshi J.; Gleave, Martin; Chi, Kim N.; Reiter, Robert E.; Rettig, Matthew B.; Evans, Christopher P.; Small, Eric J.; Sharifi, Nima; Zhao, Shuang G.

    In: Prostate Cancer and Prostatic Diseases, 01.01.2019.

    Research output: Contribution to journalArticle

    Chen, WS, Feng, EL, Aggarwal, R, Foye, A, Beer, TM, Alumkal, JJ, Gleave, M, Chi, KN, Reiter, RE, Rettig, MB, Evans, CP, Small, EJ, Sharifi, N & Zhao, SG 2019, 'Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer', Prostate Cancer and Prostatic Diseases. https://doi.org/10.1038/s41391-019-0188-4
    Chen, William S. ; Feng, Eric L. ; Aggarwal, Rahul ; Foye, Adam ; Beer, Tomasz M. ; Alumkal, Joshi J. ; Gleave, Martin ; Chi, Kim N. ; Reiter, Robert E. ; Rettig, Matthew B. ; Evans, Christopher P. ; Small, Eric J. ; Sharifi, Nima ; Zhao, Shuang G. / Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer. In: Prostate Cancer and Prostatic Diseases. 2019.
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    title = "Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer",
    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.",
    author = "Chen, {William S.} and Feng, {Eric L.} and Rahul Aggarwal and Adam Foye and Beer, {Tomasz M.} and Alumkal, {Joshi J.} and Martin Gleave and Chi, {Kim N.} and Reiter, {Robert E.} and Rettig, {Matthew B.} and Evans, {Christopher P.} and Small, {Eric J.} and Nima Sharifi and Zhao, {Shuang G.}",
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    T1 - Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer

    AU - Chen, William S.

    AU - Feng, Eric L.

    AU - Aggarwal, Rahul

    AU - Foye, Adam

    AU - Beer, Tomasz M.

    AU - Alumkal, Joshi J.

    AU - Gleave, Martin

    AU - Chi, Kim N.

    AU - Reiter, Robert E.

    AU - Rettig, Matthew B.

    AU - Evans, Christopher P.

    AU - Small, Eric J.

    AU - Sharifi, Nima

    AU - Zhao, Shuang G.

    PY - 2019/1/1

    Y1 - 2019/1/1

    N2 - 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.

    AB - 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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