Multivitamin use and risk of prostate cancer recurrence: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 70-70
Author(s):  
Erin Van Blarigan ◽  
Stacey A. Kenfield ◽  
Benjamin E Cedars ◽  
Jenny Broering ◽  
Janet E. Cowan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lower Risk ◽  
Proportional Hazards ◽  
Cancer Recurrence ◽  
Primary Treatment ◽  
Cox Proportional Hazards ◽  
Age At Diagnosis ◽  
P Value ◽  
Gleason Grade

70 Background: Multivitamin (MV) use is common among men with prostate cancer (PCa). Yet, data on MV use and risk of PCa recurrence are limited. Methods: We conducted a prospective study among 1,373 men with non-metastatic PCa to examine whether MV use after diagnosis was associated with risk of recurrence. Participants completed a comprehensive lifestyle survey a median of 2 y after diagnosis and were followed through 2016. We defined an event of recurrence as the first of the following: PCa death, bone metastasis from PCa, biochemical recurrence, or initiation of secondary treatment. Multivariate Cox Proportional Hazards regression models were used to calculate hazards ratios (HRs) and 95% confidence intervals (CI) for the association between MV use and PCa recurrence. We adjusted for time between diagnosis and the survey, age at diagnosis, Gleason grade, clinical T-stage, PSA at diagnosis, smoking, BMI, walking pace, and primary treatment. We also explored whether age at diagnosis, BMI, time since diagnosis, smoking, or clinical features (grade, stage, treatment) modified the association between MV use and recurrence. Results: We observed 142 events of PCa recurrence over a median follow-up of 10 y; 858 (62%) men were current MV users, 216 (16%) were past users, and 299 (22%) were never users. Overall, MV use was not associated with risk of PCa recurrence (current vs. never HR: 0.69; 95% CI: 0.45, 1.07; p-trend: 0.09). However, long-term MV users (≥10 y; n = 396) had a 56% lower risk of PCa recurrence compared to never users (HR: 0.44; 95% CI: 0.25, 0.78; p-trend: 0.006). Additionally, treatment modified the association between MV use and risk of PCa recurrence ( p-interaction: 0.02). Among the 845 men who had a radical prostatectomy (RP), current MV users had a 44% lower risk of PCa recurrence compared to past/never users (HR: 0.56; 95% CI: 0.34, 0.91; p-value: 0.02). MV use was not associated with risk of PCa recurrence among the 441 men who did not have a RP. Conclusions: Long-term MV use may be associated with lower risk of PCa recurrence.

Milk and other dairy foods in relation to prostate cancer progression: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE).

2017 ◽  
Vol 35 (5_suppl) ◽  
pp. 168-168
Author(s):  
David Tat ◽  
Erin Van Blarigan ◽  
Stacey A. Kenfield ◽  
Jenny Broering ◽  
Janet E. Cowan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
P Value ◽  
High Fat ◽  
Low Fat ◽  
Dairy Foods ◽  
Whole Milk ◽  
Increased Risk

168 Background: Recent research suggests a positive relationship between intake of high-fat dairy, particularly whole milk, and prostate cancer (PC) mortality. However, data are limited in men after PC diagnosis. Methods: We conducted a prospective cohort study among 1336 men with non-metastatic PC in CaPSURE. The men answered a food frequency questionnaire (FFQ) in 2004-2005 (median time from diagnosis to the FFQ: 2 y) and were followed for PC progression until April 2016. PC progression was defined as: prostate cancer death, bone metastasis from PC, biochemical recurrence, or secondary treatment. Multivariate Cox Proportional Hazards regression was used to calculate hazards ratios (HR) and 95% confidence intervals (CI) for associations between total, whole fat, and low-fat milk; total, high-fat, and low-fat dairy; and specific dairy items and PC progression. We adjusted for time from diagnosis to FFQ, calories, age at diagnosis, CAPRA score, smoking, BMI, walking pace, and primary PC treatment. Results: 314 events were observed (mean follow-up: 7.2 y). Whole milk was associated with an increased risk of PC progression when adjusting for age, calories, and time since diagnosis (HR ≥1 vs. <1 serving/wk: 1.37; 95% CI: 1.03, 1.84; p-value: 0.03). This association was slightly attenuated, and not statistically significant, when adjusting for clinical and other lifestyle factors (HR: 1.27; 95% CI: 0.91, 1.77; p-value: 0.15). High-fat dairy intake also appeared associated with an increased risk of PC progression, but the association was not statistically significant (adjusted HR ≥4 vs. <1 servings/day: 1.40; 95% CI: 0.92, 2.13; p-trend: 0.18). Post-diagnostic intakes of low-fat milk and other dairy foods were not associated with PC progression. Conclusions: Post-diagnostic intake of milk and other dairy foods was not associated with PC progression. Research in populations with greater intake of whole milk is warranted to further investigate whether post-diagnostic whole milk intake increases risk of PC progression. Funding: This work was funded by the DOD Prostate Cancer Research Program (W81XWH-13-2-0074) and the NIH (K07CA197077).

scholarly journals Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer

2017 ◽  
Vol 177 (4) ◽  
pp. 297-308 ◽  
Author(s):  
Yi X Chan ◽  
Matthew W Knuiman ◽  
Mark L Divitini ◽  
Suzanne J Brown ◽  
John Walsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Skin Cancer ◽  
Thyroid Hormones ◽  
Lower Risk ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Community Dwelling ◽  
Free Thyroxine ◽  
Increased Risk

Context Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk. Objectives To explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers. Design and setting A prospective cohort study of a community-dwelling population aged 25–84 years in Western Australia. Main outcome measures Archived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression. Results During 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 mIU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55–0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03–1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer. Conclusion In a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.

scholarly journals African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

2020 ◽  
Author(s):  
Roshan Karunamuni ◽  
Minh-Phuong Huynh-Le ◽  
Chun Fan ◽  
Wesley Thompson ◽  
Rosalind Eeles ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Proportional Hazards ◽  
Performance Metrics ◽  
Association Studies ◽  
Cox Proportional Hazards ◽  
Genetic Ancestry ◽  
Age At Diagnosis ◽  
Genome Wide Association Studies ◽  
Relative Hazard ◽  
Genome Wide

AbstractIntroductionPolygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.ResultsThree SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.

scholarly journals Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in older adults

2021 ◽  
Author(s):  
Katia J Bruxvoort ◽  
Bradley Ackerson ◽  
Lina S Sy ◽  
Amit Bhavsar ◽  
Hung Fu Tseng ◽  
...  
Keyword(s):  
Lower Risk ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Innate Immune Responses ◽  
Zoster Vaccine ◽  
Kaiser Permanente ◽  
Cohort Design ◽  
Hazard Ratios ◽  
Negative Controls

Background: Vaccines may elicit long-term boosting of innate immune responses that can help protect against COVID-19. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and COVID-19 outcomes at Kaiser Permanente Southern California. Methods: In a cohort design, adults aged ≥50 years who received ≥1 RZV dose prior to 3/1/2020 were matched 1:2 to unvaccinated individuals and followed until 12/31/2020. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive SARS-CoV-2 test and controls had only negative tests, from 3/1/2020-12/31/2020. Adjusted odds ratios (aOR) and 95% CIs for prior receipt of RZV were estimated using logistic regression. Results: In the cohort design, 149,244 RZV recipients were matched to 298,488 unvaccinated individuals. The aHRs (95% CI) for COVID-19 diagnosis and hospitalization were 0.84 (0.81-0.87) and 0.68 (0.64-0.74), respectively. In the test-negative design, 8.4% of 75,726 test-positive cases and 13.1% of 340,898 test-negative controls had received ≥1 RZV dose. The aOR (95% CI) was 0.84 (0.81-0.86). Conclusion: RZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization, suggesting RZV elicits heterologous protection, possibly through trained immunity.

Abstract 4881: Interaction of Genetic and Pharmacologic β -adrenergic Signaling Inhibitors Determines Long-term Mortality after Acute Coronary Ischemia

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sharon Cresci ◽  
Reagan Kelly ◽  
Sharon Kardia ◽  
John A Spertus ◽  
Gerald W Dorn
Keyword(s):  
Proportional Hazards ◽  
Experimental Models ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Carrier Status ◽  
Human Heart Failure ◽  
Time To Death ◽  
Risk Of Death ◽  
Protein Receptor

Introduction: While chronic β-blocker (BB) therapy after myocardial infarction (MI) reduces the long-term risk of death, recent studies suggest that BB within 24h after MI is associated with increased death from cardiogenic shock. We have described a naturally-occurring G-protein Receptor Kinase ( GRK )5 L41 polymorphism that mimics BB effects in experimental models and human heart failure raising the possibility that pre-existing “genetic β-blockade” might also affect outcomes after MI. Methods: 3,244 patients hospitalized with acute coronary ischemic syndromes (ACS; 2,943 MI; 301 unstable angina) were followed for an average of 2.7 years. Primary endpoint was time to death. A sub-cohort (n=973) was followed for time to rehospitalization. Independent variables were antecedent BB therapy (a-BB), discharge BB therapy (d-BB), and GRK5 Q41L genotype. Differences were assessed with Kaplan Meier curves, log-rank tests, and Cox proportional hazards modeling (HR). Results: Complete data were available for 2,732 subjects (24% African American [AA], 33% female, 32% a-BB, 87% d-BB). Overall mortality rate was 12%, and rehospitalization occurred in 41%. AA had increased mortality risk (HR=1.32, CI= 1.017–1.71, p=0.037). a-BB significantly increased mortality in both AA (HR=1.69, CI=1.006–2.84, p=0.047) and Caucasians (HR=1.98, CI=1.523–2.57, p=0.00000033). GRK5 L41 is more common in AA. GRK5 L41 carrier status did not significantly affect mortality in AA or Caucasian non-BB subjects, but protected against death in AA with a-BB (HR=0.456, CI= 0.256 – 0.812, p=0.0076; p value for gene-drug interaction=0.041). In the rehospitalization sub-study, GRK5 L41 protected AA from rehospitalization, independent of BB use (HR=0.605, CI=0.388 – 0.943, p=0.026). d-BB status was not associated with mortality or rehospitalization after discharge. Conclusions: Antecedent, but not discharge, treatment with BB is associated with adverse long-term outcomes in ACS patients requiring hospitalization. In contrast, AA patients carrying the GRK5 L41 polymorphism are protected against death and rehospitalization. “Genetic β-blockade” may have advantages over, and can oppose some untoward consequences of, pharmacological β-receptor antagonism in ACS patients.

scholarly journals Depression and long-term prognostic outcomes following peripheral endovascular interventions in the VA Healthcare System

2018 ◽  
Vol 23 (5) ◽  
pp. 454-460 ◽  
Author(s):  
Kim G Smolderen ◽  
Mary E Plomondon ◽  
Ehrin J Armstrong ◽  
Edward Hess ◽  
Stephen Waldo ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Vascular Intervention ◽  
Endovascular Interventions ◽  
Increased Risk ◽  
Peripheral Vascular Intervention ◽  
Artery Disease

The association between depression and peripheral artery disease (PAD) outcomes remains widely understudied. In patients with PAD undergoing a peripheral vascular intervention (PVI) who have a recent diagnosis of depression, it is unknown what their long-term outcomes are and what factors may mediate an adverse risk. We therefore studied 797 consecutive patients undergoing PVI across 33 Veterans Affairs (VA) centers. Depression and outcomes were documented from patients’ medical records. Outcomes included: (1) all-cause death; (2) non-fatal cardiovascular events (myocardial infarction, stroke); and (3) PAD-related events (including repeat PVI or amputation). Cox proportional hazards frailty models were constructed, adjusting for age. Additional covariates were selected if they resulted in at least 5% change in the age-adjusted hazard ratio (HR) for depression on outcomes. Overall, 265 (33%) patients had a diagnosis of depression. After a median follow-up of 955 days (range 1–6.25 years), 52 (6.5%) patients died, 30 (3.8%) experienced non-fatal cardiovascular events, and 176 (22.1%) had PAD-related events. Compared to patients without depression, depressed patients had higher rates of non-fatal cardiovascular events (6.4% vs 2.4%, p-value 0.0055). No differences for the other outcomes were noted. Higher risk for non-fatal cardiovascular events persisted after adjustment for age (HR 1.6, 95% CI 1.05–2.47). The only additional covariate that met our selection criteria was hypertension. After adjusting for hypertension, the association between depression and non-fatal cardiovascular outcomes attenuated (HR 1.53, 95% CI 0.99–2.35). In conclusion, a diagnosis of depression in veterans undergoing PVI was associated with increased risk of non-fatal cardiovascular events, mediated by age and hypertension.

scholarly journals Multi-omic serum biomarkers for prognosis of disease progression in prostate cancer

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Michael A. Kiebish ◽  
Jennifer Cullen ◽  
Prachi Mishra ◽  
Amina Ali ◽  
Eric Milliman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Predictive Value ◽  
Proportional Hazards ◽  
Prognostic Markers ◽  
Oncological Outcome ◽  
Predictive Performance ◽  
Primary Treatment ◽  
Cox Proportional Hazards ◽  
Serum Samples

Abstract Background Predicting the clinical course of prostate cancer is challenging due to the wide biological spectrum of the disease. The objective of our study was to identify prostate cancer prognostic markers in patients ‘sera using a multi-omics discovery platform. Methods Pre-surgical serum samples collected from a longitudinal, racially diverse, prostate cancer patient cohort (N = 382) were examined. Linear Regression and Bayesian computational approaches integrated with multi-omics, were used to select markers to predict biochemical recurrence (BCR). BCR-free survival was modeled using unadjusted Kaplan–Meier estimation curves and multivariable Cox proportional hazards analysis, adjusted for key pathologic variables. Receiver operating characteristic (ROC) curve statistics were used to examine the predictive value of markers in discriminating BCR events from non-events. The findings were further validated by creating a training set (N = 267) and testing set (N = 115) from the cohort. Results Among 382 patients, 72 (19%) experienced a BCR event in a median follow-up time of 6.9 years. Two proteins—Tenascin C (TNC) and Apolipoprotein A1V (Apo-AIV), one metabolite—1-Methyladenosine (1-MA) and one phospholipid molecular species phosphatidic acid (PA) 18:0-22:0 showed a cumulative predictive performance of AUC = 0.78 [OR (95% CI) = 6.56 (2.98–14.40), P < 0.05], in differentiating patients with and without BCR event. In the validation set all four metabolites consistently reproduced an equivalent performance with high negative predictive value (NPV; > 80%) for BCR. The combination of pTstage and Gleason score with the analytes, further increased the sensitivity [AUC = 0.89, 95% (CI) = 4.45–32.05, P < 0.05], with an increased NPV (0.96) and OR (12.4) for BCR. The panel of markers combined with the pathological parameters demonstrated a more accurate prediction of BCR than the pathological parameters alone in prostate cancer. Conclusions In this study, a panel of serum analytes were identified that complemented pathologic patient features in predicting prostate cancer progression. This panel offers a new opportunity to complement current prognostic markers and to monitor the potential impact of primary treatment versus surveillance on patient oncological outcome.

scholarly journals Long-term Clinical Outcomes in Favorable Risk Prostate Cancer Patients Receiving Proton Beam Therapy

2021 ◽  
Author(s):  
Alicia Bao ◽  
Andrew R. Barsky ◽  
Russell Maxwell ◽  
Justin E. Bekelman ◽  
Stefan Both ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Control ◽  
Proton Beam ◽  
Proportional Hazards ◽  
Proton Beam Therapy ◽  
Cox Proportional Hazards ◽  
Biochemical Failure ◽  
Distant Failure ◽  
Regional Failure

Abstract Purpose Long-term data regarding the disease control outcomes of proton beam therapy (PBT) for patients with favorable risk intact prostate cancer (PC) are limited. Herein, we report our institution's long-term disease control outcomes in PC patients with clinically localized disease who received PBT as primary treatment. Methods One hundred sixty-six favorable risk PC patients who received definitive PBT to the prostate gland at our institution from 2010 to 2012 were retrospectively assessed. The outcomes studied were biochemical failure-free survival (BFFS), biochemical failure, local failure, regional failure, distant failure, PC-specific survival, and overall survival. Patterns of failure were also analyzed. Multivariate Cox proportional hazards modeling was used to estimate independent predictors of BFFS. Results The median length of follow-up was 8.3 years (range, 1.2–10.5 years). The majority of patients had low-risk disease (58%, n = 96), with a median age of 64 years at the onset of treatment. Of 166 treated men, 13 (7.8%), 8 (4.8%), 2 (1.2%) patient(s) experienced biochemical failure, local failure, regional failure, respectively. Regional failure was seen in an obturator lymph node in 1 patient and the external iliac lymph nodes in the other. None of the patients experienced distant failure. There were 5 (3.0%) deaths, none of which were due to PC. The 5- and 8-year BFFS rate were 97% and 92%, respectively. None of the clinical disease characteristics or treatment-related factors assessed were associated with BFFS on multivariate Cox proportional hazards modeling (all P &gt; .05). Conclusion Disease control rates reported in our assessment of PBT were similar to those reported in previous clinically localized intact PC analyses, which used intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, or radical prostatectomy as definitive therapy. In addition, BFFS rates were similar, if not improved, to previous PBT studies.

Project data sphere (PDS) in prostate cancer: A first look including concomitant medication use.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 204-204
Author(s):  
Bethany Gill ◽  
Leila Khoja ◽  
Zhu Juan Li ◽  
Robert James Hamilton ◽  
Marianne Koritzinsky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Concomitant Medication ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Prognostic Models ◽  
P Value ◽  
Metastatic Site ◽  
Concomitant Medications

204 Background: PDS enables patient-level analyses of control arms of cancer trials. The interface (www.projectdatasphere.org) allows for both web-based and download-based analyses. We aimed to validate established prostate cancer prognostic models and explore the effect of concomitant medications on survival in mCRPC. Methods: Data was obtained for 2,747 control subjects with mCRPC from 7 Phase III clinical trials with 1962 subjects available for OS analyses from 5 studies. Overall survival was estimated using the Kaplan-Meier Method. Cox-proportional hazards models, stratified by trial, were used to estimate hazard ratios. Results: Metastatic site was significant for overall survival (Median: Node only 23.69m, Bone 18.17m, Lung 14.72m, Liver 9.43m; p < 0.001). Of the 23 types of medication examined, after adjusting for metastatic site, patients taking proton pump inhibitors (HR: 1.155, p=0.017) and Erythropoietin (HR: 1.49, p-value<.001) had worse overall survival whilst patients taking fish oil (HR:0.68, p-value=0.033) and non-lipophilic statins (HR:0.69, p=.00277) had improved overall survival. Within the limits of available data, we validated the prognostic models for overall survival proposed by Templeton et al. and Sonpavde et al individually and after inclusion of concomitant medication where patients taking metformin (HR=0.729, p=.0082) and Cox 2 inhibitors (HR=0.708, p=.015) had improved OS whilst those taking low molecular weight heparin (HR=1.352, p=.004) had worse OS. Conclusions: As a first project utilizing open-source PDS data in prostate cancer, we validated two prostate cancer prognostic models and illuminated the ability to undertake novel analyses such as the association of concomitant medications with outcome. Limitations of the data relate to incomplete and inconsistent data entry. Future expansion of patient trials and numbers will help to facilitate future analyses.

scholarly journals The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy

2014 ◽  
Vol 22 (1) ◽  
pp. 77-85 ◽  
Author(s):  
Isabelle Laverdière ◽  
Christine Flageole ◽  
Étienne Audet-Walsh ◽  
Patrick Caron ◽  
Yves Fradet ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Proportional Hazards ◽  
Prognostic Significance ◽  
Cancer Recurrence ◽  
Cox Proportional Hazards ◽  
Estrogen Metabolism ◽  
Nucleotide Polymorphisms ◽  
Functional Polymorphisms ◽  
Risk Alleles ◽  
Caucasian Men

The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at theUGT1locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants ofUGT1are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across theUGT1locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan–Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for fourUGT1intronic variants with hazard ratios (HRs) of 1.59–1.88 (P<0.002) for htSNPs inUGT1A10,UGT1A9, andUGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns ofUGT1A10andUGT1A9(HR=0.56–058;P≤0.01). An unfavorableUGT1haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13–2.50;P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms ofUGT1are potential predictors of recurrence of PCa after prostatectomy.

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