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Alison Mondul

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Papers by Alison Mondul

Vitamin D binding protein and risk of renal cell carcinoma in the prostate, lung, colorectal and ovarian cancer screening trial

International Journal of Cancer, 2019

Our group has conducted two previous studies on the association between vitamin D binding protein... more Our group has conducted two previous studies on the association between vitamin D binding protein (DBP) and renal cell carcinoma (RCC), the most common form of kidney cancer, finding strong inverse associations. We undertook the current analysis to replicate our findings in a different study population that included women and nonsmokers. We conducted a nested case–control study in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cases (n = 323) were matched 1:1 to controls on age (±1 year), race/ethnicity, date of blood collection (±30 days) and sex. We performed conditional logistic regression to estimate the odds ratios and 95% confidence intervals for the association between quartiles of circulating DBP and risk of RCC. We observed a statistically significant positive association between DBP and RCC that persisted after adjustment for history of diabetes, history of hypertension, family history of renal cancer, body mass index and smoking status (mv‐adj Q...

Pre-diagnostic Serum Metabolomic Profiling of Prostate Cancer Survival

The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 7, 2018

Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a co... more Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a comprehensive analysis of the interrelationships appears lacking. We measured 625 metabolites using ultrahigh performance LC/MS-GC/MS of prediagnostic serum from 197 prostate cancer cases in the ATBC Study (ages at diagnosis, 55-86 years). Cox proportional hazards models estimated associations between circulating metabolites and prostate cancer mortality for 1-standard deviation (SD) differences (log-metabolite scale), adjusted for age, year of diagnosis, and disease stage. Associations between metabolite chemical classes and survival were examined through pathway analysis, and Cox models assessed the relationship with a sterol/steroid metabolite principal component analysis factor score. Elevated serum N-oleoyl taurine was significantly associated with prostate cancer-specific mortality (HR=1.72 per 1-SD, p<0.00008, Bonferroni corrected threshold=0.05/625; HR=3.6 for highest vs lowest ...

Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study

Cancer Prevention Research, 2018

Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer.... more Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer. Fatal prostate cancer, the most clinically relevant outcome, remains understudied for this association. We prospectively studied lipid-lowering medication use and both incident and fatal prostate cancer in black and white men in the Atherosclerosis Risk in Communities (ARIC) study. A total of 6,518 men without cancer at visit 2 (1990–1992), the start of the statin era, were followed for prostate cancer incidence and death through 2012. Medication use was collected during study visits and telephone calls at up to nine time points during follow-up. Cox regression was used to estimate HR and 95% confidence intervals (CI) of total (white N = 541, black N = 259) and fatal (white N = 56, black N = 34) prostate cancer overall and by race. Lipid-lowering medication use was modeled as time-dependent current use or duration (never, <10, and ≥10 years). By visit 4 (1996–1998), 21% of white and ...

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

International journal of epidemiology, Oct 14, 2016

Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and ot... more Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. Baseline serum 25-hydroxy-vitamin D [25(OH)D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH)D levels. A majority of the metabolites associated with 25(OH)D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpro...

Vitamins, metabolomics, and prostate cancer

World Journal of Urology, 2016

Purpose-How micronutrients might influence risk of developing adenocarcinoma of the prostate has ... more Purpose-How micronutrients might influence risk of developing adenocarcinoma of the prostate has been the focus of a large body of research (especially regarding vitamins E, A, and D). Metabolomic profiling has the potential to discover molecular species relevant to prostate cancer etiology, early detection, and prevention, and may help elucidate the biologic mechanisms by which vitamins influence prostate cancer risk. Methods-Prostate cancer risk data related to vitamins E, A, and D and metabolomics profiling from clinical, cohort, and nested case-control studies, along with randomized controlled trials, are examined and summarized, along with recent metabolomic data of the vitamin phenotypes. Results-Higher vitamin E serologic status is associated with lower prostate cancer risk, and vitamin E genetic variant data support this. By contrast, controlled vitamin E supplementation trials have mixed results based on differing designs and dosages. Beta-carotene supplementation (in smokers) and higher circulating retinol and 25-hydroxy-vitamin D concentrations appear related to elevated prostate cancer risk. Our prospective metabolomics profiling of fasting serum collected 1-20 years prior to clinical diagnoses found lipid and energy/TCA cycle metabolites, including inositol-1-phosphate, lysolipids, alpha-ketoglutarate, and citrate, significantly associated with risk of aggressive disease. Conclusions-Several active leads exist regarding the role of micronutrients and metabolites in prostate cancer carcinogenesis and risk. How vitamins D and A may adversely impact risk, and whether low-dose vitamin E supplementation remains a viable preventive approach, require further study.

Association of serum a-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk

Cancer Cause Control, 2011

Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies

The American journal of clinical nutrition, Jan 7, 2015

Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be as... more Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated wi...

Abstract 5069: Circulating 25-hydroxyvitamin D and prostate cancer survival

Cancer Research, 2014

Background: Basic research suggests that vitamin D may inhibit prostate tumorigenesis through a n... more Background: Basic research suggests that vitamin D may inhibit prostate tumorigenesis through a number of mechanisms, including enhanced cellular differentiation and apoptosis, but epidemiological studies do not indicate an inverse circulating vitamin D-prostate cancer risk association. However, low circulating 25-hydroxyvitamin D [25(OH)D] concentrations, the accepted biomarker of vitamin D status, have been associated with reduced prostate cancer survival. Methods: We examined circulating 25(OH)D in relation to prostate cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish men. Among 1,000 participants diagnosed with prostate cancer through April 2005, 359 had died, with mortality follow-up through December 2012. 25(OH)D was measured in fasting serum samples prospectively drawn at the study baseline, using the DiaSorin LIAISON 25(OH)D TOTAL assay, with interbatch and intrabatch CVs of 12.3% and 10.5%, respectively. Age-adjusted proportion...

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocopherol, beta-carotene cancer prevention study

International journal of cancer. Journal international du cancer, Jan 22, 2015

Despite decades of concerted epidemiological research, relatively little is known about the etiol... more Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome-wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, "broad-spectrum" approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort based on 200 cases (100 advanced) and 200 controls (age- and blood collection date-matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men, and the odds ratio per 1-standard deviation increase in log-metabolite levels and risk were estimated using conditional logistic regression. We observed ...

Vitamin D-associated genetic variation and risk of breast cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 26, 2014

Background:Two recent genome-wide association studies (GWAS) identified SNPs related to circulati... more Background:Two recent genome-wide association studies (GWAS) identified SNPs related to circulating 25-hydroxyvitamin D [25(OH)D] concentration in or near four genes. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods:SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results:We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions:Our findings do not support an association between vitamin D status, as reflected by 25(OH)D-related genotypes, and breast cancer risk. Impact: The...

Circulating Thyroxine, Thyroid-Stimulating Hormone, and Hypothyroid Status and the Risk of Prostate Cancer

PLoS ONE, 2012

Background: Thyroid hormones may influence risk of cancer through their role in cell differentiat... more Background: Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Within the ATBC Study, a randomized controlled trial of a-tocopherol and b-carotene supplements and cancer incidence in male smokers, 402 prostate cancer cases were sampled. Controls were matched 2:1 to cases on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer were estimated for quintiles of serum total and free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid-binding globulin (TBG), and by categories of thyroid status. Results: Men with serum higher TSH had a decreased risk of prostate cancer compared to men with lower TSH (Q5 vs. Q1-4: OR = 0.70, 95% CI: 0.51-0.97, p = 0.03). When the T4 and TSH measurements were combined to define men as hypothyroid, euthyroid or hyperthyroid, hypothyroid men had a lower risk of prostate cancer compared to euthyroid men (OR = 0.48, 95% CI = 0.28-0.81, p = 0.006). We observed no association between hyperthyroid status and risk, although the number of hyperthyroid men with prostate cancer was small (n = 9). Conclusions: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethnic groups.

1-Stearoylglycerol is associated with risk of prostate cancer: results from a serum metabolomic profiling analysis

Metabolomics, 2014

Association of Statin Use With Pathological Tumor Characteristics and Prostate Cancer Recurrence After Surgery

Journal of Urology, 2011

Purpose-Prospective studies suggest that statins protect against advanced stage and possibly high... more Purpose-Prospective studies suggest that statins protect against advanced stage and possibly high grade prostate cancer. However, few studies have investigated the influence of stains on outcomes in men with prostate cancer. Thus, we evaluated the association of statin use with pathological tumor characteristics and prostate cancer recurrence after prostatectomy in a retrospective cohort. Materials and Methods-A total of 2,399 patients of 1 surgeon at Johns Hopkins Hospital who underwent radical prostatectomy in 1993 to 2006 and had not previously received hormone or radiation therapy were followed for recurrence. The surgeon routinely asked during the preoperative consultation what medications the men were using. Additional information on statin use was obtained from a mailed survey. We estimated the association of statin use with nonorgan confined disease (pT3a/b or N1) and high grade disease (Gleason sum [4 + 3] or greater) using logistic regression (OR), and recurrence using Cox proportional hazards regression (HR). Results-The 16.1% of men who used a statin at prostatectomy were statistically significantly less likely to have nonorgan confined disease than nonusers (OR 0.66, 95% CI 0.50-0.85). Statin use was inversely associated with high grade disease only in men with preoperative PSA 10 ng/ml or greater (OR 0.35, 95% CI 0.13-0.93, p-interaction = 0.02). The HR of recurrence among men who used a statin for 1 year or greater compared to nonusers was 0.77 (95% CI 0.41-1.42). Conclusions-Our findings support the hypothesis that statin use may protect against prostate cancer with poorer pathological characteristics. We could not rule in or out that longer term statin use may protect against recurrence after prostatectomy.

A Prospective Study of Obesity, and the Incidence and Progression of Lower Urinary Tract Symptoms

Journal of Urology, 2014

Purpose-We prospectively evaluated the association between adiposity and risk of lower urinary tr... more Purpose-We prospectively evaluated the association between adiposity and risk of lower urinary tract symptoms (LUTS) incidence and progression in the Health Professionals Follow-up Study (HPFS). Materials and Methods-Participants reported their current height and weight and their weight at age 21 at baseline, a year later their waist and hip circumferences, and then every two years their weight. Periodically, participants completed the International Prostate Symptom Score (IPSS) survey and reported surgery or medication use for LUTS. We used Cox proportional hazards regression to estimate the multivariable-adjusted association between adiposity and LUTS incidence and progression. The incidence analytic cohort (n=18,055) were men without LUTS at baseline. Men entered the progression analytic cohort (n=6,461) when they first experienced LUTS. Results-Risk of LUTS (n=4,088) increased with increasing body mass index (BMI ≥35 vs 23-<25 kg/m 2 : HR=1.61; 95% CI 1.31-1.99, p-trend<0.0001), waist circumference (>42 vs ≤33 in: HR=1.39, 95% CI 1.19-1.63, p-trend<0.0001), and weight gain from age 21 (≥50 lbs vs stable weight: HR=1.31, 95% CI 1.17-1.46, p-trend=<0.0001). Risk of LUTS progression (n=1,691) increased with BMI (≥35 vs 23-<25 kg/m 2 : HR=1.44, 95% CI 1.04-2.00, p-trend=<0.0001), weight gain from 21 years of age (≥50 lbs vs stable weight: HR=1.35, 95% CI 1.14-1.60, p-trend=<0.0001), and waist circumference (>42 vs ≤33 in: HR=1.32, 95% CI 0.95-1.85, p-trend=0.005). Conclusions-Men with higher total and abdominal adiposity or who gained weight were more likely to develop LUTS or experience progressive LUTS. Our findings support that obesity may be an important target for LUTS prevention and intervention.

Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer

International Journal of Cancer, 2012

We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], th... more We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), and statistical tests were two-sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR=1.81, 95% CI 1.18-2.79 for highest vs. lowest quintile, ptrend = 0.001) compared to those with DBP below the median (OR=1.22, 95% CI 0.81-1.84, ptrend 0.97; p-interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR=0.96, 95% CI 0.70-1.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower (<median) 25(OH)D concentrations (OR=0.59, 95% CI 0.38-0.90 for highest vs. lowest quintile, p-trend = 0.003) and increased risk in men with higher 25(OH)D concentrations (OR = 1.47, 95% CI 0.98-2.20, p-trend 0.10, p-interaction = 0.02). Our data suggest that the primary vitamin D carrier protein, DBP, modulates the impact of vitamin D status on prostate cancer.

Serum Vitamin D and Risk of Bladder Cancer

Cancer Research, 2010

Vitamin D may protect against several cancers, but data about the association between circulating... more Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e., <25, 25 to <37.5, 37.5 to <50, ≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L; <25 nmol/L: OR, 1.73; 95% C...

Minimal detection bias in the inverse association between statin drug use and advanced prostate cancer risk: A simulation study

Cancer Epidemiology, 2011

Background-Prospective studies support that statins may protect against advanced prostate cancer.... more Background-Prospective studies support that statins may protect against advanced prostate cancer. Detection bias arising from higher PSA screening rates among statin users vs. non-users could produce an inverse association for advanced disease. Thus, we conducted simulations to assess whether this source of bias is explanatory. Methods-3,000 datasets with 100,000 men without prostate cancer were simulated for populations with high (65%) or low (15%) PSA screening. We investigated three scenarios: RR true = 1.0, 0.75, and 0.5 for statins and advanced disease (1.0 for localized). We set the statin prevalence to 10% and varied the percentage of users who were PSA screened (0-100%). We assumed an annual total prostate cancer incidence of 1%, with risk in screened men twice that of unscreened men, and an advanced stage at diagnosis in 20% and 40% of cases in screened and unscreened men, respectively. Results-As PSA screening and statin use became more coincident, the RR observed for local and total prostate cancer was biased upward from the RR true of 1.0, especially when the prevalence of PSA screening was low. However, in all simulated scenarios, there was little downward bias for advanced disease (e.g., if RR true = 1.0 and 70% of statin users and either 65% or 15% of the population overall was PSA screened, then RR observed = 0.98 for both). Conclusions-Given our assumptions, this simulation suggests that this source of detection bias is unlikely to explain the reported inverse association between statins and advanced prostate cancer, but may explain the positive association for total prostate cancer that has been reported in some studies.

Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer—Results from the Breast and Prostate Cancer Cohort Consortium

Cancer Epidemiology, Biomarkers & Prevention, 2013

Background: Studies suggest that vitamin D status may be associated with prostate cancer risk alt... more Background: Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer. Results: We observed a decreased risk of aggressive prostate cancer among men with the allele in rs601389...

Serum Vitamin D and Risk of Bladder Cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Cancer Epidemiology, Biomarkers & Prevention, 2012

Background: The one previous prospective study of vitamin D status and risk of urinary bladder ca... more Background: The one previous prospective study of vitamin D status and risk of urinary bladder cancer found that male smokers with low serum 25-hydroxy-vitamin D [25(OH)D] were at a nearly two-fold increased risk. We conducted an analysis of serum 25(OH)D and risk of bladder cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study and examined whether serum vitamin D binding protein (DBP) concentration confounded or modified the association. Methods: Three hundred and seventy-five cases of bladder cancer were matched 1:1 with controls based on age (±5 years), race, sex, and date of blood collection (±30 days). Conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) of bladder cancer by prediagnosis levels of 25(OH)D. Results: We found no strong or statistically significant association between serum 25(OH)D and bladder cancer risk (Q1 vs. Q4: OR, 0.84; 95% CI, 0.52–1.36; Ptrend = 0.56). Further adjustment for, or stratific...

Serum 25-Hydroxy Vitamin D and Prostate Cancer Risk in a Large Nested Case–Control Study

Cancer Epidemiology, Biomarkers & Prevention, 2011

Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic ... more Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. Methods: The 25-hydroxy vitamin D [25(OH)D]–prostate cancer relation was examined in a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (±1 year) and fasting blood collection date (±30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56 (1.15–2.12), with Ptr...

Vitamin D binding protein and risk of renal cell carcinoma in the prostate, lung, colorectal and ovarian cancer screening trial

International Journal of Cancer, 2019

Our group has conducted two previous studies on the association between vitamin D binding protein... more Our group has conducted two previous studies on the association between vitamin D binding protein (DBP) and renal cell carcinoma (RCC), the most common form of kidney cancer, finding strong inverse associations. We undertook the current analysis to replicate our findings in a different study population that included women and nonsmokers. We conducted a nested case–control study in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cases (n = 323) were matched 1:1 to controls on age (±1 year), race/ethnicity, date of blood collection (±30 days) and sex. We performed conditional logistic regression to estimate the odds ratios and 95% confidence intervals for the association between quartiles of circulating DBP and risk of RCC. We observed a statistically significant positive association between DBP and RCC that persisted after adjustment for history of diabetes, history of hypertension, family history of renal cancer, body mass index and smoking status (mv‐adj Q...

Pre-diagnostic Serum Metabolomic Profiling of Prostate Cancer Survival

The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 7, 2018

Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a co... more Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a comprehensive analysis of the interrelationships appears lacking. We measured 625 metabolites using ultrahigh performance LC/MS-GC/MS of prediagnostic serum from 197 prostate cancer cases in the ATBC Study (ages at diagnosis, 55-86 years). Cox proportional hazards models estimated associations between circulating metabolites and prostate cancer mortality for 1-standard deviation (SD) differences (log-metabolite scale), adjusted for age, year of diagnosis, and disease stage. Associations between metabolite chemical classes and survival were examined through pathway analysis, and Cox models assessed the relationship with a sterol/steroid metabolite principal component analysis factor score. Elevated serum N-oleoyl taurine was significantly associated with prostate cancer-specific mortality (HR=1.72 per 1-SD, p<0.00008, Bonferroni corrected threshold=0.05/625; HR=3.6 for highest vs lowest ...

Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study

Cancer Prevention Research, 2018

Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer.... more Lipid-lowering medications, particularly statins, may protect against aggressive prostate cancer. Fatal prostate cancer, the most clinically relevant outcome, remains understudied for this association. We prospectively studied lipid-lowering medication use and both incident and fatal prostate cancer in black and white men in the Atherosclerosis Risk in Communities (ARIC) study. A total of 6,518 men without cancer at visit 2 (1990–1992), the start of the statin era, were followed for prostate cancer incidence and death through 2012. Medication use was collected during study visits and telephone calls at up to nine time points during follow-up. Cox regression was used to estimate HR and 95% confidence intervals (CI) of total (white N = 541, black N = 259) and fatal (white N = 56, black N = 34) prostate cancer overall and by race. Lipid-lowering medication use was modeled as time-dependent current use or duration (never, <10, and ≥10 years). By visit 4 (1996–1998), 21% of white and ...

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

International journal of epidemiology, Oct 14, 2016

Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and ot... more Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. Baseline serum 25-hydroxy-vitamin D [25(OH)D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH)D levels. A majority of the metabolites associated with 25(OH)D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpro...

Vitamins, metabolomics, and prostate cancer

World Journal of Urology, 2016

Purpose-How micronutrients might influence risk of developing adenocarcinoma of the prostate has ... more Purpose-How micronutrients might influence risk of developing adenocarcinoma of the prostate has been the focus of a large body of research (especially regarding vitamins E, A, and D). Metabolomic profiling has the potential to discover molecular species relevant to prostate cancer etiology, early detection, and prevention, and may help elucidate the biologic mechanisms by which vitamins influence prostate cancer risk. Methods-Prostate cancer risk data related to vitamins E, A, and D and metabolomics profiling from clinical, cohort, and nested case-control studies, along with randomized controlled trials, are examined and summarized, along with recent metabolomic data of the vitamin phenotypes. Results-Higher vitamin E serologic status is associated with lower prostate cancer risk, and vitamin E genetic variant data support this. By contrast, controlled vitamin E supplementation trials have mixed results based on differing designs and dosages. Beta-carotene supplementation (in smokers) and higher circulating retinol and 25-hydroxy-vitamin D concentrations appear related to elevated prostate cancer risk. Our prospective metabolomics profiling of fasting serum collected 1-20 years prior to clinical diagnoses found lipid and energy/TCA cycle metabolites, including inositol-1-phosphate, lysolipids, alpha-ketoglutarate, and citrate, significantly associated with risk of aggressive disease. Conclusions-Several active leads exist regarding the role of micronutrients and metabolites in prostate cancer carcinogenesis and risk. How vitamins D and A may adversely impact risk, and whether low-dose vitamin E supplementation remains a viable preventive approach, require further study.

Association of serum a-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk

Cancer Cause Control, 2011

Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies

The American journal of clinical nutrition, Jan 7, 2015

Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be as... more Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated wi...

Abstract 5069: Circulating 25-hydroxyvitamin D and prostate cancer survival

Cancer Research, 2014

Background: Basic research suggests that vitamin D may inhibit prostate tumorigenesis through a n... more Background: Basic research suggests that vitamin D may inhibit prostate tumorigenesis through a number of mechanisms, including enhanced cellular differentiation and apoptosis, but epidemiological studies do not indicate an inverse circulating vitamin D-prostate cancer risk association. However, low circulating 25-hydroxyvitamin D [25(OH)D] concentrations, the accepted biomarker of vitamin D status, have been associated with reduced prostate cancer survival. Methods: We examined circulating 25(OH)D in relation to prostate cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish men. Among 1,000 participants diagnosed with prostate cancer through April 2005, 359 had died, with mortality follow-up through December 2012. 25(OH)D was measured in fasting serum samples prospectively drawn at the study baseline, using the DiaSorin LIAISON 25(OH)D TOTAL assay, with interbatch and intrabatch CVs of 12.3% and 10.5%, respectively. Age-adjusted proportion...

Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocopherol, beta-carotene cancer prevention study

International journal of cancer. Journal international du cancer, Jan 22, 2015

Despite decades of concerted epidemiological research, relatively little is known about the etiol... more Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome-wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, "broad-spectrum" approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort based on 200 cases (100 advanced) and 200 controls (age- and blood collection date-matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men, and the odds ratio per 1-standard deviation increase in log-metabolite levels and risk were estimated using conditional logistic regression. We observed ...

Vitamin D-associated genetic variation and risk of breast cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 26, 2014

Background:Two recent genome-wide association studies (GWAS) identified SNPs related to circulati... more Background:Two recent genome-wide association studies (GWAS) identified SNPs related to circulating 25-hydroxyvitamin D [25(OH)D] concentration in or near four genes. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts. Methods:SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer. Results:We found no association between any of the four SNPs or their polygenic score and breast cancer risk. Conclusions:Our findings do not support an association between vitamin D status, as reflected by 25(OH)D-related genotypes, and breast cancer risk. Impact: The...

Circulating Thyroxine, Thyroid-Stimulating Hormone, and Hypothyroid Status and the Risk of Prostate Cancer

PLoS ONE, 2012

Background: Thyroid hormones may influence risk of cancer through their role in cell differentiat... more Background: Thyroid hormones may influence risk of cancer through their role in cell differentiation, growth, and metabolism. One study of circulating thyroid hormones supports this hypothesis with respect to prostate cancer. We undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Within the ATBC Study, a randomized controlled trial of a-tocopherol and b-carotene supplements and cancer incidence in male smokers, 402 prostate cancer cases were sampled. Controls were matched 2:1 to cases on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer were estimated for quintiles of serum total and free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroid-binding globulin (TBG), and by categories of thyroid status. Results: Men with serum higher TSH had a decreased risk of prostate cancer compared to men with lower TSH (Q5 vs. Q1-4: OR = 0.70, 95% CI: 0.51-0.97, p = 0.03). When the T4 and TSH measurements were combined to define men as hypothyroid, euthyroid or hyperthyroid, hypothyroid men had a lower risk of prostate cancer compared to euthyroid men (OR = 0.48, 95% CI = 0.28-0.81, p = 0.006). We observed no association between hyperthyroid status and risk, although the number of hyperthyroid men with prostate cancer was small (n = 9). Conclusions: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethnic groups.

1-Stearoylglycerol is associated with risk of prostate cancer: results from a serum metabolomic profiling analysis

Metabolomics, 2014

Association of Statin Use With Pathological Tumor Characteristics and Prostate Cancer Recurrence After Surgery

Journal of Urology, 2011

Purpose-Prospective studies suggest that statins protect against advanced stage and possibly high... more Purpose-Prospective studies suggest that statins protect against advanced stage and possibly high grade prostate cancer. However, few studies have investigated the influence of stains on outcomes in men with prostate cancer. Thus, we evaluated the association of statin use with pathological tumor characteristics and prostate cancer recurrence after prostatectomy in a retrospective cohort. Materials and Methods-A total of 2,399 patients of 1 surgeon at Johns Hopkins Hospital who underwent radical prostatectomy in 1993 to 2006 and had not previously received hormone or radiation therapy were followed for recurrence. The surgeon routinely asked during the preoperative consultation what medications the men were using. Additional information on statin use was obtained from a mailed survey. We estimated the association of statin use with nonorgan confined disease (pT3a/b or N1) and high grade disease (Gleason sum [4 + 3] or greater) using logistic regression (OR), and recurrence using Cox proportional hazards regression (HR). Results-The 16.1% of men who used a statin at prostatectomy were statistically significantly less likely to have nonorgan confined disease than nonusers (OR 0.66, 95% CI 0.50-0.85). Statin use was inversely associated with high grade disease only in men with preoperative PSA 10 ng/ml or greater (OR 0.35, 95% CI 0.13-0.93, p-interaction = 0.02). The HR of recurrence among men who used a statin for 1 year or greater compared to nonusers was 0.77 (95% CI 0.41-1.42). Conclusions-Our findings support the hypothesis that statin use may protect against prostate cancer with poorer pathological characteristics. We could not rule in or out that longer term statin use may protect against recurrence after prostatectomy.

A Prospective Study of Obesity, and the Incidence and Progression of Lower Urinary Tract Symptoms

Journal of Urology, 2014

Purpose-We prospectively evaluated the association between adiposity and risk of lower urinary tr... more Purpose-We prospectively evaluated the association between adiposity and risk of lower urinary tract symptoms (LUTS) incidence and progression in the Health Professionals Follow-up Study (HPFS). Materials and Methods-Participants reported their current height and weight and their weight at age 21 at baseline, a year later their waist and hip circumferences, and then every two years their weight. Periodically, participants completed the International Prostate Symptom Score (IPSS) survey and reported surgery or medication use for LUTS. We used Cox proportional hazards regression to estimate the multivariable-adjusted association between adiposity and LUTS incidence and progression. The incidence analytic cohort (n=18,055) were men without LUTS at baseline. Men entered the progression analytic cohort (n=6,461) when they first experienced LUTS. Results-Risk of LUTS (n=4,088) increased with increasing body mass index (BMI ≥35 vs 23-<25 kg/m 2 : HR=1.61; 95% CI 1.31-1.99, p-trend<0.0001), waist circumference (>42 vs ≤33 in: HR=1.39, 95% CI 1.19-1.63, p-trend<0.0001), and weight gain from age 21 (≥50 lbs vs stable weight: HR=1.31, 95% CI 1.17-1.46, p-trend=<0.0001). Risk of LUTS progression (n=1,691) increased with BMI (≥35 vs 23-<25 kg/m 2 : HR=1.44, 95% CI 1.04-2.00, p-trend=<0.0001), weight gain from 21 years of age (≥50 lbs vs stable weight: HR=1.35, 95% CI 1.14-1.60, p-trend=<0.0001), and waist circumference (>42 vs ≤33 in: HR=1.32, 95% CI 0.95-1.85, p-trend=0.005). Conclusions-Men with higher total and abdominal adiposity or who gained weight were more likely to develop LUTS or experience progressive LUTS. Our findings support that obesity may be an important target for LUTS prevention and intervention.

Circulating 25-hydroxyvitamin D, vitamin D-binding protein and risk of prostate cancer

International Journal of Cancer, 2012

We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], th... more We recently reported a significant positive association between 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), and statistical tests were two-sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR=1.81, 95% CI 1.18-2.79 for highest vs. lowest quintile, ptrend = 0.001) compared to those with DBP below the median (OR=1.22, 95% CI 0.81-1.84, ptrend 0.97; p-interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR=0.96, 95% CI 0.70-1.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower (<median) 25(OH)D concentrations (OR=0.59, 95% CI 0.38-0.90 for highest vs. lowest quintile, p-trend = 0.003) and increased risk in men with higher 25(OH)D concentrations (OR = 1.47, 95% CI 0.98-2.20, p-trend 0.10, p-interaction = 0.02). Our data suggest that the primary vitamin D carrier protein, DBP, modulates the impact of vitamin D status on prostate cancer.

Serum Vitamin D and Risk of Bladder Cancer

Cancer Research, 2010

Vitamin D may protect against several cancers, but data about the association between circulating... more Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e., <25, 25 to <37.5, 37.5 to <50, ≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L; <25 nmol/L: OR, 1.73; 95% C...

Minimal detection bias in the inverse association between statin drug use and advanced prostate cancer risk: A simulation study

Cancer Epidemiology, 2011

Background-Prospective studies support that statins may protect against advanced prostate cancer.... more Background-Prospective studies support that statins may protect against advanced prostate cancer. Detection bias arising from higher PSA screening rates among statin users vs. non-users could produce an inverse association for advanced disease. Thus, we conducted simulations to assess whether this source of bias is explanatory. Methods-3,000 datasets with 100,000 men without prostate cancer were simulated for populations with high (65%) or low (15%) PSA screening. We investigated three scenarios: RR true = 1.0, 0.75, and 0.5 for statins and advanced disease (1.0 for localized). We set the statin prevalence to 10% and varied the percentage of users who were PSA screened (0-100%). We assumed an annual total prostate cancer incidence of 1%, with risk in screened men twice that of unscreened men, and an advanced stage at diagnosis in 20% and 40% of cases in screened and unscreened men, respectively. Results-As PSA screening and statin use became more coincident, the RR observed for local and total prostate cancer was biased upward from the RR true of 1.0, especially when the prevalence of PSA screening was low. However, in all simulated scenarios, there was little downward bias for advanced disease (e.g., if RR true = 1.0 and 70% of statin users and either 65% or 15% of the population overall was PSA screened, then RR observed = 0.98 for both). Conclusions-Given our assumptions, this simulation suggests that this source of detection bias is unlikely to explain the reported inverse association between statins and advanced prostate cancer, but may explain the positive association for total prostate cancer that has been reported in some studies.

Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer—Results from the Breast and Prostate Cancer Cohort Consortium

Cancer Epidemiology, Biomarkers & Prevention, 2013

Background: Studies suggest that vitamin D status may be associated with prostate cancer risk alt... more Background: Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer. Results: We observed a decreased risk of aggressive prostate cancer among men with the allele in rs601389...

Serum Vitamin D and Risk of Bladder Cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Cancer Epidemiology, Biomarkers & Prevention, 2012

Background: The one previous prospective study of vitamin D status and risk of urinary bladder ca... more Background: The one previous prospective study of vitamin D status and risk of urinary bladder cancer found that male smokers with low serum 25-hydroxy-vitamin D [25(OH)D] were at a nearly two-fold increased risk. We conducted an analysis of serum 25(OH)D and risk of bladder cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study and examined whether serum vitamin D binding protein (DBP) concentration confounded or modified the association. Methods: Three hundred and seventy-five cases of bladder cancer were matched 1:1 with controls based on age (±5 years), race, sex, and date of blood collection (±30 days). Conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) of bladder cancer by prediagnosis levels of 25(OH)D. Results: We found no strong or statistically significant association between serum 25(OH)D and bladder cancer risk (Q1 vs. Q4: OR, 0.84; 95% CI, 0.52–1.36; Ptrend = 0.56). Further adjustment for, or stratific...

Serum 25-Hydroxy Vitamin D and Prostate Cancer Risk in a Large Nested Case–Control Study

Cancer Epidemiology, Biomarkers & Prevention, 2011

Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic ... more Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. Methods: The 25-hydroxy vitamin D [25(OH)D]–prostate cancer relation was examined in a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (±1 year) and fasting blood collection date (±30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56 (1.15–2.12), with Ptr...