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

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

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.70 ◽

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.

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Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study

Cancers ◽

10.3390/cancers13081958 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1958

Author(s):

Anna E. Prizment ◽

Sean McSweeney ◽

Nathan Pankratz ◽

Corinne E. Joshu ◽

Justin H. Hwang ◽

...

Keyword(s):

Prostate Cancer ◽

Proportional Hazards ◽

Risk Allele ◽

Genetic Risk Score ◽

Cumulative Effect ◽

Population Based ◽

Cox Proportional Hazards ◽

Nucleotide Polymorphisms ◽

Gain Of Function ◽

Specific Mortality

Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.

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Pathologic and biochemical outcomes among African American and Caucasian men with low-risk prostate cancer in the search database: Implications for active surveillance candidacy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.76 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 76-76

Author(s):

Michael S. Leapman ◽

Stephen J. Freedland ◽

William J Aaronson ◽

Christopher J. Kane ◽

Martha K. Terris ◽

...

Keyword(s):

Prostate Cancer ◽

African American ◽

Biochemical Recurrence ◽

Proportional Hazards ◽

Clinical Stage ◽

Cox Proportional Hazards ◽

Low Risk ◽

Equal Access ◽

Caucasian Race ◽

Caucasian Men

76 Background: Racial disparities in the incidence and risk profile of prostate cancer (PCa) at diagnosis among African American (AA) men are well reported, however it remains unclear whether AA race is independently associated with adverse pathological findings among men with clinical low risk disease. Methods: We conducted a retrospective analysis among 895 men, with clinical low risk (Gleason 3+3, clinical stage ≤T2a, PSA≤10 ng/mL) treated with immediate radical prostatectomy within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. We evaluated clinical and demographic characteristics by AA or Caucasian race. Associations between AA versus Caucasian race with pathologic Gleason upgrade (≥3+4), major upgrade (≥4+3), upstage (pT3a or higher), margin status and biochemical recurrence (BCR) were examined using chi-square, logistic regression, log-rank, and Cox proportional hazards analyses. Results: We identified 355 AA and 540 Caucasian men with low-risk tumors within the SEARCH cohort followed for a median of 6.3 (IQR 3.8-8.9). AA men were younger (mean 59.5vs. 62.0 years), and had higher median PSA (5.5 vs. 5.1). Following adjustment for relevant covariates, AA race was not significantly associated with pathological upgrade (OR 1.335, 95% CI 0.936-1.905, p=0.111), major upgrade (OR 0.561, 95% CI 0.300-1.049, p=0.070), upstaging (OR 1.111, 95% CI 0.670-1.844, p=0.683), or positive surgical margins (OR 1.046, 95% CI 0.732-1.494, p=0.806). The 5-year recurrence-free survival rates were 73.4% and 78.4% for AA and Caucasian men, respectively (log-rank p=0.178). After adjustment for clinical and pathological characteristics, AA race was not significantly associated with BCR (HR 1.1.054, 95% CI 0.814-1.501, p=0.521). Conclusions: In a cohort of low-risk men treated with prostatectomy within an equal access health system with a high representation of AA men, no significant differences were observed in the rates of pathologic upgrading, upstaging or biochemical recurrence. These data support continued use of AS in AA. Upgrading and upstaging remain concerning possibilities for all men regardless of race.

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Small Extracellular Vesicle-Derived microRNAs Stratify Prostate Cancer Patients According to Gleason Score, Race and Associate with Survival of African American and Caucasian Men

Cancers ◽

10.3390/cancers13205236 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5236

Author(s):

Hamdy E. A. Ali ◽

Mohamed S. A. Gaballah ◽

Rofaida Gaballa ◽

Shahenda Mahgoub ◽

Zeinab A. Hassan ◽

...

Keyword(s):

Prostate Cancer ◽

African American ◽

Gleason Score ◽

Proportional Hazards ◽

Extracellular Vesicle ◽

Cox Proportional Hazards ◽

Independent Prognostic Marker ◽

Clinical Biomarkers ◽

Caucasian Men ◽

Prognostic Utility

The utility of small extracellular vesicles (sEVs)-derived microRNAs (miRs) to segregate prostate cancer (PCa) patients according to tumor aggressiveness and ancestral background has not been fully investigated. Thus, we aimed to determine the diagnostic and prognostic utility of sEV-associated miRs in identifying aggressive PCa in African American (AA) and Caucasian (CA) men. Using a training cohort, miR profiling was performed on sEVs isolated from plasma of PCa patients. Top-ranked sEV-associated miRs were then validated in 150 plasma samples (75 AA and 75 CA) collected from two independent cohorts; NIH (n = 90) and Washington University (n = 60) cohorts. Receiver operating characteristic (ROC) curve, Kaplan–Meier and Cox proportional hazards regression were used to assess these miRs as clinical biomarkers. Among nine top-ranked sEV-associated miRs, miR-6068 and miR-1915-3p were enriched in sEVs collected from PCa patients compared to healthy volunteers. Moreover, miR-6716-5p and miR-3692-3p segregated AA from CA men and low from high Gleason score (GS), respectively. Upregulation of sEV-associated miR-1915-3p, miR-3692-3p and miR-5001-5p was associated with improved survival time, and only miR-1915-3p was associated with longer recurrence-free survival (RFS) as an independent prognostic marker. Taken together, we identified novel sEV-associated miRs that can differentiate PCa patients from normal, AA from CA and high from low GS and predicts RFS.

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Combination of Polymorphisms From Genes Related to Estrogen Metabolism and Risk of Prostate Cancers: The Hidden Face of Estrogens

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.0908 ◽

2007 ◽

Vol 25 (24) ◽

pp. 3596-3602 ◽

Cited By ~ 70

Author(s):

Olivier Cussenot ◽

Abdel Rhamene Azzouzi ◽

Nathalie Nicolaiew ◽

Gaelle Fromont ◽

Philippe Mangin ◽

...

Keyword(s):

Prostate Cancer ◽

Age At Onset ◽

Prostate Cancer Risk ◽

Estrogen Metabolism ◽

Genetic Profiling ◽

Functional Polymorphisms ◽

Risk Alleles ◽

History Of ◽

Disease Stratification ◽

Prostate Cancers

Purpose The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated. Patients and Methods The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers. Results The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients. Conclusion This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways.

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Risk and Timing of Cardiovascular Disease After Androgen-Deprivation Therapy in Men With Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.59.1792 ◽

2015 ◽

Vol 33 (11) ◽

pp. 1243-1251 ◽

Cited By ~ 121

Author(s):

Sean O'Farrell ◽

Hans Garmo ◽

Lars Holmberg ◽

Jan Adolfsson ◽

Pär Stattin ◽

...

Keyword(s):

Prostate Cancer ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Gnrh Agonists ◽

Cvd Risk ◽

Comparison Cohort ◽

Using Data

Purpose Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. Methods By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. Results From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. Conclusion Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.

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Abstract T MP48: Androgen Suppression in Patients with Prostate Cancer Increases Incidence of Combined Cardiovascular Outcomes

Stroke ◽

10.1161/str.46.suppl_1.tmp48 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Zuber S Ali ◽

Danielle M Greere ◽

Robyn L Shearer ◽

Syed Ali Gardezi ◽

Arshad Jahangir

Keyword(s):

Prostate Cancer ◽

Proportional Hazards ◽

Age Groups ◽

The Elderly ◽

Cox Proportional Hazards ◽

Cardiovascular Outcomes ◽

Elevated Risk ◽

Disease Stage ◽

Cox Proportional Hazards Models ◽

Androgen Suppression

Introduction: Androgen suppression therapy for prostate cancer is controversial due to adverse fatal and non-fatal cardiovascular outcomes reported in some studies. However, effects of androgen suppression on stroke have not been fully assessed in the elderly. Methods: Patients diagnosed with prostate cancer during 2007-2013 in a large community-based healthcare system were identified from the Cancer Registry, electronic records, and billing codes. Those who underwent androgen suppression therapy with Gonadotropin-releasing hormone agonist (GnRH) were propensity-matched to patients treated without androgen suppression therapy by age at cancer diagnosis, race/ethnicity, disease stage and outcome, body mass index and use of surgery, radiation, and chemotherapy. Tests of independence and Cox proportional hazards models were used to examine effects of hormone therapy on acute myocardial infarction (AMI), stroke, and mortality outcomes. Models also adjusted for patient comorbidities. Results: A total of 1282 patients and 641 matched-pairs were identified, with mean diagnosis age of 69 yr and follow-up period of 3.05 yr. Effects of androgen suppression therapy on AMI (P=0.051) and stroke (P=0.062) were of marginal to non-significance, but adjusted-odds of death and combined AMI, stroke, and death were 1.61 times (P=0.002; odds ratio [OR] 95% CI: 1.19-2.18) and 1.70 times (P<0.001; OR 95% CI: 1.26-2.28) greater, respectively, for men with than without androgen suppression. An interaction of androgen suppression and age-group (<65 yr, 65-74 yr, >74 yr) was discovered for combined outcomes, suggesting increased probability of AMI, stroke, and/or death with age (8.6-20.0%; P=0.003) for patients without androgen suppression but elevated risk of outcomes across all age groups (18.3-22.4%; P=0.546) for men treated with androgen suppression therapy. Conclusion: Endogenous androgen suppression presents elevated risk of combined cardiovascular and death outcomes, especially for men <65 yr.

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Histopathologic Features that Predict Transplant Glomerulopathy Progression in a Chinese Cohort

American Journal of Nephrology ◽

10.1159/000500043 ◽

2019 ◽

Vol 49 (6) ◽

pp. 425-434 ◽

Cited By ~ 2

Author(s):

Xue Li ◽

Jinsong Chen ◽

Dongrui Cheng ◽

Wei Wang ◽

Kenan Xie ◽

...

Keyword(s):

Primary Outcome ◽

Proportional Hazards ◽

Linear Regression Analysis ◽

Prognostic Significance ◽

Immunoglobulin A ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

Chinese Cohort ◽

Transplant Glomerulopathy ◽

Histopathologic Features

Background: Transplant glomerulopathy (TG) represents a major cause of long-term allograft failure and is the leading cause of overall post-transplant proteinuria. The extent to which histopathologic features predicts prognostication is uncertain. Methods: A single-center retrospective cohort with biopsy-proven TG was investigated. Renal biopsies were scored according to Banff 2017. The primary outcome was death-censored graft failure defined as return to dialysis or estimated glomerular filtration rate (eGFR) decreased to <15 mL/min/1.73 m2. The prognostic significance of clinical and histopathologic parameters was determined using Cox proportional hazards models. Results: Data from 180 cases were available for analysis with a median follow-up of 5.0 (2.6–8.2) years. In multivariable models, ci + ct score (HR 3.1; 95% CI 2.0–4.9), cg score (HR 1.7; 95% CI 1.1–2.8), eGFR (HR 2.1; 95% CI 1.4–3.2) and proteinuria (HR 2.4; 95% CI 1.6–3.7) were independent predictors of the primary outcome. Mesangial Immunoglobulin A deposition did not significantly affect allograft survival. The only significant pathologic factors for the severity of proteinuria were cg and g + ptc (adjusted R2 = 0.46) as determined by multivariable stepwise linear regression analysis. Conclusions: Severe ci + ct and cg at biopsy were predictors of unfavorable allograft prognosis in TG patients even after taking into consideration clinical characteristics. Histologic severity of cg and g + ptc was significantly associated with clinical proteinuria.

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Prostate cancer-specific survival differences in patients treated by radical prostatectomy versus curative radiotherapy

Canadian Urological Association Journal ◽

10.5489/cuaj.1245 ◽

2013 ◽

Vol 7 (5-6) ◽

pp. 299 ◽

Cited By ~ 10

Author(s):

Julie M. DeGroot ◽

Michael D. Brundage ◽

Miu Lam ◽

Susan L. Rohland ◽

Jeremy Heaton ◽

...

Keyword(s):

Prostate Cancer ◽

Proportional Hazards ◽

Risk Groups ◽

Cox Proportional Hazards ◽

Intermediate Risk ◽

Cancer Specific Survival ◽

Entire Study ◽

Curative Radiotherapy ◽

The Impact ◽

Cause Specific Survival

Objective: We compared the cause-specific survival of patientswho received radiotherapy to those who received surgery for cureof their prostate cancer using a number of design and analytic stepsto mitigate confounding by indication.Methods: This was a case-cohort study of 2213 patients in theOntario Cancer Registry diagnosed between 1990 and 1998 whowere either treatment candidates or received curative radiotherapyor surgery. Cases included patients who died of prostate cancerwithin 10 years. The study population was restricted to those whowere candidates for either treatment (radiotherapy or surgery)based on disease severity (low and intermediate risk using theGenitourinary Radiation Oncologists of Canada risk groups). Themedian follow-up was 51 months. Cause-specific survival wasanalyzed using Cox-proportional hazards regression with casecohortvariance adjustment.Results from intent-to-treat analyseswere compared to results by treatment received.Results: Adjusted hazard ratios for risk of prostate cancer death forradiotherapy compared to surgery for the entire study populationwere 1.62 (95%CI 1.00-2.61) and 2.02 (1.19-3.43) analyzing byintent-to-treat and treatment received, respectively. Intent-to-treathazard ratios for the low- and intermediate-risk groups were 0.87(0.28-2.76) and 1.57 (0.95-2.61), respectively.Conclusion: Overall results were driven by the finding in the intermediate-risk group, which indicated that radiotherapy was not aseffective as surgery in this group. Confirmation was needed withspecial attention paid to risk stratification and the impact of morecontemporary delivery of these treatment options.

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