Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer.
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ABSTRACT:
SUBMITTER: Shiota M
PROVIDER: S-EPMC8119070 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Chronic inflammation is an important mechanism for the development and progression of prostate cancer (PC). To better understand the potential relationship between genes in the inflammation pathway and PC risk, we evaluated variants in 16 candidate genes. METHODS:A total of 143 tagging and amino acid altering single nucleotide polymorphisms (SNPs) were genotyped in Caucasian and African American men participating in one of two population-based, case-control studies (n = 1,458 cases and 1,351 controls). The relative risk of PC was estimated using logistic and polytomous regression models. RESULTS:Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen with rs11574783 in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). Cumulatively, four SNPs in genes interleukin 4 (IL4), IL6ST, PTGS2, and signal transducer and activator of transcription 3 (STAT3) conferred a three-fold elevation in PC risk among men carrying the maximum number of high-risk alleles (OR = 2.97, 95% CI: 1.41-6.25, P(trend) = 0.0003). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (P(homogeneity) < 0.05), with SNPs in AKT1, PIK3R1, and STAT3 independently associated with more aggressive PC; OR = 5.1 (95% CI: 2.29-11.40, P(trend) = 3.8 × 10(-5)) for carriers of all high-risk genotypes. CONCLUSIONS:These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, however, further studies are needed to replicate our findings. IMPACT:These results underline the potential importance of the inflammation pathway in PC development and progression.
| S-EPMC3140053 | biostudies-literature
Project description:The fibroblast growth factor receptor 4 (FGFR4) is thought to be involved in many critical cellular processes and has been associated with prostate cancer risk. Four single nucleotide polymorphisms (SNPs) within or near FGFR4 were analyzed in a population-based study of 1458 prostate cancer patients and 1352 age-matched controls. We found no evidence to suggest that any of the FGFR4 SNP genotypes were associated with prostate cancer risk or with disease aggressiveness, Gleason score or stage. A weak association was seen between rs351855 and prostate cancer-specific mortality. Subset analysis of cases that had undergone radical prostatectomy revealed an association between rs351855 and prostate cancer risk. Although our results confirm an association between FGFR4 and prostate cancer risk in radical prostatectomy cases, they suggest that the role of FGFR4 in disease risk and outcomes at a population-based level appears to be minor.
| S-EPMC2790323 | biostudies-literature
Project description:Megalin, an endocytic receptor expressed by prostate epithelial cells, can internalize biologically active androgens bound to sex hormone binding globulin. Genetic variation within megalin could potentially influence levels of steroid hormone uptake.Forty haplotype-tagging single-nucleotide polymorphisms (htSNP) were analyzed in a population-based, case-control study of 553 Caucasian men who were diagnosed with prostate cancer between the ages of 40 and 64 years from the Seattle-Puget Sound region and 534 control men. Prostate cancer risk was estimated using adjusted unconditional logistic regression for both individual SNPs and haplotypes. Risks of disease recurrence/progression and prostate-specific cancer mortality were estimated using Cox proportional hazards regression.We found no strong evidence of altered risk of developing prostate cancer for any of the htSNPs when they were assessed individually or in haplotypes. However, three htSNPs were significantly associated with both disease recurrence/progression and mortality. Risk of recurrence/progression alone was also associated with five additional htSNPs, and six other htSNPS showed evidence of modification by primary androgen deprivation therapy. Two additional htSNPs were significantly associated with altered risk of death from prostate cancer.Preliminary results suggest that common genetic variation within the megalin gene could alter both risk of recurrence/progression and prostate-specific cancer mortality. In addition, androgen deprivation therapy effectiveness may be modified by the activity of this gene. To our knowledge, this is the first study that has examined polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes.
| S-EPMC2675883 | biostudies-literature
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.
| S-EPMC3623834 | biostudies-literature
Project description:In 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.Representative areas of prostate carcinoma (n?=?51) and of nodular prostate hyperplasia (n?=?20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1?), 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).Immunohistochemistry 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).Protein 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.
| S-EPMC5282787 | biostudies-literature
Project description:The hypoxia-inducible factor-1? (HIF-1?) plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIF1A (coding HIF-1?) have been shown to influence an individual's susceptibility to many human tumors; however, evidence on associations between HIF1A single-nucleotide polymorphisms (SNPs) and prostate cancer (PCa) risk is conflicting. We genotyped three potentially functional polymorphisms in HIF1A (rs11549465, rs11549467 and rs2057482) using the TaqMan method and assessed their associations with PCa risk in a case-control study of 662 PCa patients and 716 controls in a Chinese Han population. Compared with rs11549467 GG genotype, the variant genotypes GA+AA had a significantly increased PCa risk (adjusted odds ratio (OR)=1.70; 95% confidence interval (CI)=1.06-2.72), particularly among older patients (OR=2.01; 95%CI=1.05-3.86), smokers (OR=2.06; 95%CI=1.07-3.99), never drinkers (OR=2.16; 95%CI=1.20-3.86) and patients without a family history of cancer (OR=1.71; 95%CI=1.02-2.89). Furthermore, patients with rs11549467 variant genotypes were associated with a higher Gleason score (OR=2.14; 95%CI=1.22-3.75). No altered PCa risk was associated with the rs11549465 and rs2057482 polymorphism. However, the combined variant genotypes of rs2057482 and rs11549467 were associated with increased PCa risk (OR=2.10; 95%CI=1.23-3.57 among subjects carrying three or more risk alleles). These results suggest that HIF1A polymorphisms may impact PCa susceptibility and progression in the Chinese Han population.
| S-EPMC3720106 | biostudies-literature
Project description:The purpose of this study was to evaluate the association between ATM, TP53 and MDM2 polymorphisms in prostate cancer patients and morbidity after radiotherapy. The presence of ATM (rs1801516), TP53 (rs1042522, rs1800371, rs17878362, rs17883323, and rs35117667), and MDM2 (rs2279744) polymorphisms was assessed by direct sequencing of PCR fragments from 48 patients with histologically proven prostate adenocarcinoma and treated with external beam radiation. The side effects were classified according to the Radiation Therapy Oncology Group (RTOG) score. The results showed no association between clinical characteristics and the development of radiation toxicities (P > 0.05). The C>T transition in the position 16273 (intron 3) of TP53 (rs35117667) was significantly associated with the risk of acute skin toxicity (OR: 0.0072, 95% CI 0.0002-0.227, P = 0.003). The intronic TP53 polymorphism at position 16250 (rs17883323) was associated with chronic urinary toxicity (OR: 0.071, 95%CI 0.006-0.784, P = 0.032). No significant associations were found for the remaining polymorphisms (P > 0.05). The results show that clinical characteristics were not determinant on the developing of radiation sensitivity in prostate cancer patients, and intronic TP53 polymorphisms would be associated with increased acute and chronic radiation toxicities. These observations corroborate the importance of investigating the genetic profile to predict adverse side effects in patients undergoing radiotherapy.
| S-EPMC3844174 | biostudies-literature
Project description:Prostate cancer (PCa) is one of the most common cancers in men that usually develops slowly. Since diagnostic methods improved in the last decade and are highly precise, more cancers are diagnosed at an early stage. Active surveillance or watchful waiting are appealing approaches for men diagnosed with low-risk prostate cancer, and they are an antidote to the overtreatment problem and unnecessary biopsies. However, treatment depends on individual circumstances of a patient. Older hormonal therapies based on first generation antiandrogens and steroids were widely used in metastatic castration-resistant prostate cancer (mCRPC) patients prior to the implementation of docetaxel. Nowadays, accordingly to randomized clinical trials, abiraterone, enzalutamide, apalutamide. and docetaxel became first line agents administrated in the treatment of mCRPC. Furthermore, radium-223 is an optional therapy for bone-only metastasis patients. Sipuleucel-T demonstrated an overall survival benefit. However, other novel immunotherapeutics showed limitations in monotherapy. Possible combinations of new vaccines or immune checkpoint blockers with enzalutamide, abiraterone, radium-223, or docetaxel are the subject of ongoing rivalry regarding optimal therapy of prostate cancer.
| S-EPMC6963205 | biostudies-literature
Project description:Cytochrome P450 17alpha-hydroxylases-C-(17,20)-lyase (CYP17) is a key enzyme involved with the androgen biosynthesis pathway and has recently been targeted for therapy in men with advanced prostate cancer (PCa). However, studies relating prostate cancer outcomes with CYP17 gene variants have conflicting results. In this study we analyzed Single Nucleotide Polymorphisms (SNPs) spanning the CYP17 gene for association with PCa survival.The cohort was comprised of Caucasian men, aged 40-64, diagnosed with PCa between 1993 and 1996 in King County, Washington who participated in a population-based case-control study. CYP17 SNPs were selected to capture variation across the gene and known regulatory regions. PCa-specific mortality (PCSM) was obtained by linking to the SEER cancer registry. Recurrence/progression of PCa was determined from patient survey data and medical records. Cox proportional hazards regression analysis was used to generate hazard ratios for patient outcomes.Genotypes were available for 598 cases. With a median follow-up of 13.2 years, 44 PCa deaths were observed. Recurrence/progression events were observed in 30% of subjects. No genetic association with disease progression were identified. However, men with the variant A allele in rs10883783 had a 56% risk reduction in PCSM (HR 0.44, 95% CI 0.21-0.98).These data suggest that genetic variation in the CYP17 gene in Caucasian men is associated with PCa survival.
| S-EPMC2878282 | biostudies-literature
Project description:Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with Ptrend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; Ptrend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; Ptrend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (Ptrend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
| S-EPMC4111284 | biostudies-literature