Identification of Novel SNPs Associated with Risk and Prognosis in Patients with Castration-Resistant Prostate Cancer

Sissung, Tristan M.; Deeken, John F.; Leibrand, Crystal R.; Price, Douglas K.; Ehrlich, Sheryl; Steinberg, Seth M.; Liewehr, David J.; Dahut, William L.; Figg, William D.

doi:10.2217/pgs-2016-0134

Cited by 5 publications

(7 citation statements)

References 32 publications

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“…This study validated that rs1045642 in ABCB1 , rs9340799 in ESR1 , and rs1395 in SLC5A6 are associated with TTP in men treated with docetaxel 22–24 . P‐glycoprotein encoded by ABCB1 is an efflux pump of taxanes involved in treatment resistance to docetaxel 22 .…”

Section: Discussionsupporting

confidence: 69%

“…Additionally, the estrogen receptor α encoded by ESR1 can affect cellular sensitivity to docetaxel through survival signaling modulated by estrogen, as supported by estrogen's effect on taxane cytotoxicity in prostate cancer cells 23,26 . However, the functional link between the sodium‐dependent vitamin transporter SLC5A6 and the anticancer effect of docetaxel is unknown 24 . In addition, this study revealed, for the first time, that rs34550074 in SLCO2A1 , rs4149117 in SLCO1B3 , and rs6051545 in GNRH2 were associated with TTP in docetaxel chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Genetic variations predicting progression with docetaxel and novel androgen‐receptor pathway inhibitors

et al. 2023

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Genetic variations represented by single‐nucleotide polymorphisms (SNPs) could be helpful for choosing an effective treatment for patients with prostate cancer. This study investigated the prognostic and predictive values of SNPs associated with the prognoses of pharmacotherapy for prostate cancer through their pharmacological mechanisms. Patients treated with docetaxel or androgen receptor pathway inhibitors (ARPIs), such as abiraterone and enzalutamide, for castration‐resistant prostate cancer were included. The SNPs of interest were genotyped for target regions. The prognostic and predictive values of the SNPs for time to progression (TTP) were examined using the Cox hazard proportional model and interaction test, respectively. Rs1045642 in ABCB1, rs1047303 in HSD3B1, rs1856888 in HSD3B1, rs523349 in SRD5A2, and rs34550074 in SLCO2A1 were differentially associated with TTP between docetaxel chemotherapy and ARPI treatment. In addition to rs4775936 in CYP19A1, rs1128503 in ABCB1 and rs1077858 in SLCO2B1 might be differentially associated with TTP between abiraterone and enzalutamide treatments. Genetic predictive models using these SNPs showed a differential prognosis for treatments. This study identified SNPs that could predict progression as well as genetic models that could predict progression when patients were treated with docetaxel versus ARPI and abiraterone versus enzalutamide. The use of genetic predictive models is expected to be beneficial in selecting the appropriate treatment for the individual patient.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Genetic variations predicting progression with docetaxel and novel androgen‐receptor pathway inhibitors

et al. 2023

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“…Hepatocytes are the only cells that convert cholesterol to bile acids ( 11 ). During the elimination of bile acids via the fecal route, new bile acids are formed from hepatic cholesterol ( 12 ). Catch-up growth occurs when LBW infants are exposed to higher levels of nutrition postnatally ( 13 ), and high-fat diets (HFDs) have been shown to contribute to postnatal catch-up growth.…”

Section: Popular Scientific Summarymentioning

confidence: 99%

The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet

Zhou

Yang

Sun

et al. 2023

Food & Nutrition Research

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Purpose: To investigate possible mechanisms underlying the greater susceptibility of lipid metabolism disorders in low birth weight (LBW) mice fed with high-fat diets (HFDs). Methods: LBW mice model was established by using the pregnancy malnutrition method. Male pups were selected from LBW and normal-birth weight (NBW) offspring at random. After 3 weeks of weaning, all offspring mice were fed with HFD. Serum triglycerides (TGs), cholesterol (TC), low density lipoprotein (LDL-C), total bile acid (TAB), non-esterified fatty acid (NEFA), and mice fecal bile acid profiles were measured. Lipid deposition in liver sections was visualized by Oil Red O staining. The weight ratio of liver, muscle, and adiposity was calculated. Tandem mass tag (TMT) combined with LC-MS/MS was used to determine the differentially expressed proteins (DEPs) of liver tissue in two groups. Bioinformatics was used for further analysis of DEPs to screen key target proteins, and then Western Blot (WB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to validate the expressions of DEPs. Results: LBW mice fed with HFD showed more severe lipid metabolism disorders in the childhood. In contrast to the NBW group, the serum bile acids and fecal ω-muricholic acid (ω-MCA) levels in the LBW group were significantly lower. LC-MS/MS analysis showed that downregulated proteins were associated with lipid metabolism, and further analysis found that these proteins are mainly concentrated in peroxisome proliferation-activated receptor (PPAR) and primary bile acid synthesis signaling pathways and are involved in cellular processes and metabolic processes through binding and catalytic functions. Bioinformatics analysis indicated that the level of Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1), PPARα, key factors of cholesterol metabolism and bile acid synthesis, as well as downstream molecules Cytochrome P450 Family 4 Subfamily A Member 14 (CYP4A14), and Acyl-Coenzyme A Oxidase 2 (ACOX2) are markedly different in the liver of LBW individuals fed with HFD, and confirmed by WB and RT-qPCR. Conclusion: LBW mice are more prone to dyslipidemia probably due to downregulated bile acid metabolism-related PPARα/CYP4A14 pathway, resulting in insufficient metabolism of cholesterol to bile acids, which, in turn, leads to elevated blood cholesterol.

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“…As genetic variability in liver enzymes is often linked to interindividual variation in liver metabolism, Sissung et al hypothesised that certain variants and genes in these pathways may be behind the risk and prognosis of CRPC [29]. Patients treated with docetaxel and thalidomide and who carried variants in ABCB11 (rs7602171 GA/AA), ABCB4 (rs2302387 CT), ABCC5 (rs939339 AG), and SLC5A6 (rs1395 GA/AA) had poor OS compared to those carrying only wild-type alleles, whereas the GSTP1 rs1799811 CT genotype was associated with prolonged OS.…”

Section: Germline Genomic Biomarkers In Research Studies For Prostmentioning

confidence: 99%

“…In this small pilot study, there was suggestive evidence that SNPs in bile acid and fat catabolism genes may be related to CRPC OS. No evidence was found that any of the aforementioned SNPs were related to risk of developing CRPC [29].…”

Section: Germline Genomic Biomarkers In Research Studies For Prostmentioning

confidence: 99%

Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation

Varnai

Koskinen

Mäntylä

et al. 2019

Genes

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Prostate cancer is the fifth leading cause of male cancer death worldwide. Although docetaxel chemotherapy has been used for more than fifteen years to treat metastatic castration resistant prostate cancer, the high inter-individual variability of treatment efficacy and toxicity is still not well understood. Since prostate cancer has a high heritability, inherited biomarkers of the genomic signature may be appropriate tools to guide treatment. In this review, we provide an extensive overview and discuss the current state of the art of pharmacogenomic biomarkers modulating docetaxel treatment of prostate cancer. This includes (1) research studies with a focus on germline genomic biomarkers, (2) clinical trials including a range of genetic signatures, and (3) their implementation in treatment guidelines. Based on this work, we suggest that one of the most promising approaches to improve clinical predictive capacity of pharmacogenomic biomarkers in docetaxel treatment of prostate cancer is the use of compound, multigene pharmacogenomic panels defined by specific clinical outcome measures. In conclusion, we discuss the challenges of integrating prostate cancer pharmacogenomic biomarkers into the clinic and the strategies that can be employed to allow a more comprehensive, evidence-based approach to facilitate their clinical integration. Expanding the integration of pharmacogenetic markers in prostate cancer treatment procedures will enhance precision medicine and ultimately improve patient outcomes.

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Identification of Novel SNPs Associated with Risk and Prognosis in Patients with Castration-Resistant Prostate Cancer

Cited by 5 publications

References 32 publications

Genetic variations predicting progression with docetaxel and novel androgen‐receptor pathway inhibitors

Genetic variations predicting progression with docetaxel and novel androgen‐receptor pathway inhibitors

The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet

Pharmacogenomic Biomarkers in Docetaxel Treatment of Prostate Cancer: From Discovery to Implementation

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