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Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer.

ABSTRACT: The therapeutic landscape of pharmacotherapy for prostate cancer has dramatically evolved, and multiple therapeutic options have become available for prostate cancer patients. Therefore, useful biomarkers to identify suitable candidates for treatment are required to maximize the efficacy of pharmacotherapy. Genetic polymorphisms such as single-nucleotide polymorphisms (SNPs) and tandem repeats have been shown to influence the therapeutic effects of pharmacotherapy for prostate cancer patients. For example, genetic polymorphisms in the genes involved in androgen receptor signaling are reported to be associated with the therapeutic outcome of androgen-deprivation therapy as well as androgen receptor-pathway inhibitors. In addition, SNPs in genes involved in drug metabolism and efflux pumps are associated with therapeutic effects of taxane chemotherapy. Thus, genetic polymorphisms such as SNPs are promising biomarkers to realize personalized medicine. Here, we overview the current findings on the influence of genetic polymorphisms on the outcome of pharmacotherapy for prostate cancer and discuss current issues as well as future visions in this field.

SUBMITTER: Shiota M

PROVIDER: S-EPMC8119070 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer.

Shiota Masaki M Akamatsu Shusuke S Narita Shintaro S Terada Naoki N Fujimoto Naohiro N Eto Masatoshi M

JMA journal 20210326 2

The therapeutic landscape of pharmacotherapy for prostate cancer has dramatically evolved, and multiple therapeutic options have become available for prostate cancer patients. Therefore, useful biomarkers to identify suitable candidates for treatment are required to maximize the efficacy of pharmacotherapy. Genetic polymorphisms such as single-nucleotide polymorphisms (SNPs) and tandem repeats have been shown to influence the therapeutic effects of pharmacotherapy for prostate cancer patients. F ...[more]

PMID: 33997443

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Project description:Prostate cancer (PCa) is the most commonly diagnosed male malignancy and the second biggest cause of cancer death in men of the Western world. Higher incidences of PCa occur in men from North America, Oceania and Western countries, whereas men from Asia and North Africa have a much lower PCa incidence rate. Investigations into this population disparity of PCa incidence, in order to identify potential preventive factors or targets for the therapeutic intervention of PCa, have found differences in both environmental and genetic variations between these populations. Environmental variations include both diet and lifestyle, which vary widely between populations. Evidence that diet comes into play has been shown by men who immigrate from Eastern to Western countries. PCa incidence in these men is higher than men in their native countries. However the number of immigrants developing PCa still doesn't match native black/white men, therefore genetic factors also contribute to PCa risk, which are supported by familial studies. There are a number of genetic polymorphisms that are differentially presented between Western and Eastern men, which are potentially associated with PCa incidence. Androgen and its receptor (AR) play a major role in PCa development and progression. In this study, we focus on genes involved in androgen biosynthesis and metabolism, as well as those associated with AR pathway, whose polymorphisms affect androgen level and biological or physiological functions of androgen. While many of the genetic polymorphisms in this androgen/AR system showed different frequencies between populations, contradictory evidences exist for most of these genes investigated individually as to the true contribution to PCa risk. More accurate measurements of androgen activity within the prostate are required and further studies need to include more African and Asian subjects. As many of these genetic polymorphisms may contribute to different steps in the same biological/physiological function of androgen and AR pathway, an integrated analysis considering the combined effect of all the genetic polymorphisms may be necessary to assess their contribution to PCa initiation and progression.

Project description:BackgroundIn this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms.MethodsRepresentative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR - 604 T > C, rs2071559).ResultsImmunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006).ConclusionsProtein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR-604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

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Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer.

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Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer.

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