Dataset Information

LHRH and LHR genotypes and prostate cancer incidence and survival.

ABSTRACT: Despite their crucial role in initiating steroid-hormone synthesis, the hypothalamic and pituitary hormones (LH, LHRH) and their receptors have received scant attention in genetic studies of hormone-related diseases. This study included 1,170 men diagnosed with prostate cancer (PC) in Los Angeles County between 1999 and 2003. LHRH and LH receptor genotypes were examined for association with PC survival. Additionally, associations with PC incidence were examined by comparing PC cases to control men of similar age and race/ethnicity. The LHR 312 G allele was found to be associated with increased PC mortality (p=0.01). Ten years after diagnosis, 16% of men carrying two copies of the G allele (genotype GG) had died of PC, compared to 11% of those with genotype AG and 9% of those with AA. In a case-control comparison, this same allele was significantly associated with decreased PC risk: OR=0.68 (95% CI: 0.49, 0.93) for genotype GG vs. AA. These results suggest that androgens may play opposing roles in PC initiation and progression, and highlight the need to include these important but overlooked genes in future studies of PC etiology, prognosis, and treatment.

SUBMITTER: Ingles SA

PROVIDER: S-EPMC3852642 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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LHRH and LHR genotypes and prostate cancer incidence and survival.

Ingles Sue Ann SA Liu Stephen V SV Pinski Jacek J

International journal of molecular epidemiology and genetics 20131128 4

Despite their crucial role in initiating steroid-hormone synthesis, the hypothalamic and pituitary hormones (LH, LHRH) and their receptors have received scant attention in genetic studies of hormone-related diseases. This study included 1,170 men diagnosed with prostate cancer (PC) in Los Angeles County between 1999 and 2003. LHRH and LH receptor genotypes were examined for association with PC survival. Additionally, associations with PC incidence were examined by comparing PC cases to control m ...[more]

PMID: 24319538

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Project description:BackgroundThe value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC.Methods/designThe trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy.DiscussionThis multicenter, prospective, randomized, exploratory phase-II trial will bring about new data regarding the efficacy and safety of abiraterone/prednisone treatment with or without continuation of LHRH therapy. In addition, further insight into the complex hormonal changes under treatment will be gained and the results of this trial may give rise to a larger phase-III trial to examine the possibility of withdrawing LHRH therapy in patients with CRPC.Trial registrationClinicalTrials.gov, ID: NCT02077634 . Registered on 9 December 2013.

Project description:PurposeTo validate the association of three previously demonstrated SLCO2B1 germline variants with time to progression (TTP) in patients receiving androgen-deprivation therapy (ADT), and to evaluate if the SLCO2B1 genetic variants impacted overall survival (OS) for prostate cancer (PC).Patients and methodsThree single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in an independent validation cohort of 616 patients with PC who were treated with ADT at the Dana-Farber Cancer Institute from 1996 to 2013. Multivariable Cox proportional hazards regression adjusting for known prognostic factors estimated the association of these genetic variants with TTP and OS in patients receiving ADT. The expression of SLCO2B1 was examined in prostatectomy samples, and the impact of SLCO2B1 expression level on DHEAS (dehydroepiandrosterone sulfate) uptake was evaluated in cell lines.ResultsThe association between exonic SNP rs12422149 and TTP in patients treated with ADT was confirmed in univariable (P = .019) and multivariable analyses (adjusted hazard ratio, 1.31; 95% CI, 1.00 to 1.72 for GG v AA/AG; P = .049). Because OS had not been previously evaluated, we examined the association in the combined initial and validation cohorts (N = 1,094). The intronic SNP rs1077858 was associated with OS in both univariable (P = .009; Bonferroni's method adjusted P = .027) and multivariable analyses (adjusted hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for GG v AA/AG; P = .012). SLCO2B1 expression in normal prostate tissue and in 22RV1 cells carrying the major allele of SNP rs1077858 was significantly lower than in cells carrying the risk allele. We show in vitro that SLCO2B1 expression levels correlated with DHEAS uptake by PC cells.ConclusionThe association of SNP rs1077858 with OS may be a result of differential SLCO2B1 expression and the consequent increased uptake of DHEAS and subsequent resistance to ADT, which, in turn, may contribute to decreased OS.

Project description:ImportanceMany studies have evaluated the long-term benefits of aspirin use; however, the association of aspirin use with cancer incidence and survival in older individuals remains uncertain. Additional population-based evidence of this association is necessary to better understand any possible protective effects of aspirin in older adults.ObjectiveTo investigate the association of aspirin use with risk of developing new cancers and site-specific cancer-associated survival in bladder, breast, esophageal, gastric, pancreatic, and uterine cancers.Design, setting, and participantsThis cohort study used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants were aged 65 years or older at baseline (1993-2001) or reached age 65 during follow-up. Data analysis was conducted from January to June 2020.Main outcomes and measuresIncidence of and survival from the investigated cancer types. Univariable and multivariable hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression modeling, adjusting for covariates. Multivariable models for incidence included time-varying covariates.ResultsA total of 139 896 individuals (mean [SD] age at baseline, 66.4 [2.4] years; 71 884 [51.4%] women; 123 824 [88.5%] non-Hispanic White individuals) were included in the analysis. During the study period, 32 580 incident cancers (1751 [5.4%] bladder, 4552 [14.0%] breast, 332 [1.0%] esophageal, 397 [1.2%] gastric, 878 [2.7%] pancreatic, and 716 [2.2%] uterine cancers) were reported. Aspirin use was not associated with incidence of any of the investigated cancer types among individuals aged 65 years or older. Multivariable regression analysis demonstrated that aspirin use at least 3 times/week was associated with increased survival among patients with bladder (HR, 0.67; 95% CI, 0.51-0.88) and breast (HR, 0.75; 95% CI, 0.59-0.96) cancers but not among those with esophageal, gastric, pancreatic, or uterine cancer. A similar association of any aspirin use with bladder (HR, 0.75; 95% CI, 0.58-0.98) and breast (HR, 0.79; 95% CI, 0.63-0.99) cancer survival was observed.Conclusions and relevanceIn the current study, any aspirin use and aspirin use at least 3 times/week was associated with improved bladder and breast cancer survival. Associations between aspirin use and incidence of any of the investigated cancers or between aspirin use and esophageal, gastric, pancreatic, or uterine cancer survival were not observed.

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LHRH and LHR genotypes and prostate cancer incidence and survival.

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LHRH and LHR genotypes and prostate cancer incidence and survival.

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