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Genetic variants in AR and SHBG and resistance to hormonal castration in prostate cancer

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Abstract

Castration resistance is a life-threatening event that may develop in prostate cancer patients with advanced disease following hormonal castration therapy (HCT). Current understanding of the molecular mechanisms behind resistance to hormonal castration suggests a role for androgen receptor signaling and bioavailability of androgens. We evaluated whether common functional polymorphisms in AR and SHBG genes associate with response to HCT. The study included 203 prostate cancer patients with advanced disease treated with hormonal castration. Genomic DNA was isolated from whole blood, and the genetic polymorphisms AR +1733 G>A and SHBG +5790 G>A were determined by real-time PCR. Genetic variants were associated with response to treatment and time to resistance to hormonal castration. Multivariate analysis showed increased risk of developing resistance to hormonal castration in homozygous GG carriers of the SHBG +5790 G>A (HR = 1.9, 95 % CI 1.1–3.3, P = 0.019) polymorphism alone and when functionally combined with AR +1733 G>A into a high AR pathway activation genetic profile (HR = 1.9, 95 % CI 1.1–3.1, P = 0.015), after adjustment for age, PSA, Gleason’s score and clinical stage. Our results suggest that the SHBG +5790 G>A polymorphism may be a useful marker to include in the pharmacogenomic profile of prostate cancer resistant to hormonal castration.

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Acknowledgments

The authors acknowledge funding from the Portuguese Foundation for Science and Technology (PTDC/SAL-FCF/71552/2006) and the Portuguese League Against Cancer—North Centre. RR was the recipient of a UICC-ICRETT Fellowship (ICR/10/079/2010). This project was partially sponsored by an unrestricted educational grant for basic research in Molecular Oncology from Novartis Oncology, Portugal.

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Authors and Affiliations

  1. Molecular Oncology Group-CI, Portuguese Institute of Oncology, Edificio Laboratorios—Piso 4, Rua Dr António Bernardino Almeida, 4200-072, Porto, Portugal

    Cátia Monteiro, Ricardo Ribeiro, Avelino Fraga & Rui Medeiros

  2. LPCC—Portuguese League Against Cancer (NRNorte), Porto, Portugal

    Cátia Monteiro, Ricardo Ribeiro & Rui Medeiros

  3. Oncology Department, Portuguese Institute of Oncology, Rua Dr António Bernardino Almeida, 4200-072, Porto, Portugal

    Marta Velho Sousa & Joaquina Maurício

  4. Genetics Laboratory, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal

    Ricardo Ribeiro

  5. Urology Department, Porto Hospital Centre, Largo Prof. Abel Salazar, 4099-001, Porto, Portugal

    Avelino Fraga

  6. ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Largo Prof. Abel Salazar, no. 2, 4099-003, Porto, Portugal

    Rui Medeiros

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  1. Cátia Monteiro
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Correspondence to Rui Medeiros.

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Monteiro, C., Sousa, M.V., Ribeiro, R. et al. Genetic variants in AR and SHBG and resistance to hormonal castration in prostate cancer. Med Oncol 30, 490 (2013). https://doi.org/10.1007/s12032-013-0490-2

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  • DOI: https://doi.org/10.1007/s12032-013-0490-2

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