Case-control Study Of Prostate Cancer Research Articles

Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

Abstract Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent. Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT). Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56). Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs. Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.

Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

BackgroundThe dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene (IFNL4-ΔG) has been associated with prostate cancer among men at increased risk of sexually transmitted infections and reported to impair viral clearance. Human herpesvirus 8 (HHV-8) seropositivity has been associated with prostate cancer in Tobago.MethodsWe examined whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent among 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based controls from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT).ResultsHHV-8 seropositivity was higher in cases than controls (11% vs. 6%) and this association was restricted to carriers of the ΔG allele (OR 2.19: 95% CI:1.38–3.48) in both African American (OR 1.96; 95% CI:1.08–3.56) and European American men (OR 2.59; 95% CI:1.20–5.56).ConclusionsHHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. This study describes HHV-8 infection as a candidate prostate cancer risk factor in men with the IFNL4-ΔG genotype and supports the hypothesis that IFNL4-ΔG is a susceptibility factor that contributes to prostate cancer.

Abstract 34: High urinary thromboxane B2 associates with lethal prostate cancer in African American men and inversely correlates with aspirin use

Abstract Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African American (AA) men, potentially contributing to lethal PC development. We previously reported that regular aspirin use is associated with a decreased risk of advanced stage disease and disease recurrence in AA patients with PC. The cancer-preventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 (TXA2) is an eicosanoid produced by the COX1 enzyme in platelets. Aspirin can inhibit metastasis by inhibiting COX1 activity and TXA2 synthesis. Hence, we assessed the role of TXA2 in the development of lethal PC. Because TXA2 is unstable, we measured its corresponding primary metabolite, urinary thromboxane B2 (TXB2), to examine the relationship of TXA2 with PC. Method: TXB2 was measured in cases (977) and controls (1022) from the NCI-MD PC Case-Control study using a mass-spectrometry-based assay. TXB2 levels were modeled into low (≤median) and high (>median) levels. We calculated risk factor-adjusted odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, adjusted hazard ratios (HR) using Cox regression and sub hazard ratios (SHR) using the Fine-Gray model. Results: We observed increased TXB2 levels in cases and an inverse relationship between levels of TXB2 and aspirin use in both cases and controls. For cases who used aspirin, the odds of having high TXB2 were reduced when compared to non-users (OR 0.46 95%CI, 0.34-0.61). This observation remained significant when stratified by race/ethnicity (AA: OR 0.36 95%CI, 0.23-0.54; EA: OR 0.58 95%CI, 0.38-0.88), indicating significant inhibition of TXB2 formation by aspirin, most notably in AA men. Further analysis showed that high TXB2 is associated with a PC case status in AA men (OR 1.44 95%CI, 1.08-1.93) but not EA men (OR 1.07 95%CI, 0.83-1.93), indicating increased TXA2 synthesis in AA men with PC compared to AA men without the disease. Also, men with high TXB2 were more likely to be diagnosed with metastasis compared to men with low TXB2 (OR 4.27 95%CI, 1.48-12.29), indicating more aggressive disease for cases with high TXB2. Furthermore, high TXB2 was associated with all-cause mortality (HR 1.56 95%CI, 1.05-2.33) and PC mortality (HR 4.02 95%CI, 1.46-11.07; SHR 2.89 95%CI, 1.03-8.11) in AA men only. Our findings indicate a distinct association between TXA2 and PC outcomes in AA men. Conclusion: Aspirin use inversely associates with high TXB2. This is of clinical interest as we report that increased TXB2 associates with PC in AA men, with aggressive PC, and with PC death which disproportionally affects AA men. This is consistent with our previous findings that aspirin may reduce lethal PC in AA men and highlights the potential benefit of aspirin for prevention of lethal PC in this high-risk group of men through inhibition of TXA2 synthesis. Citation Format: Maeve Bailey-Whyte, Ginger Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Michael B. Cook, Clayton Yates, Stefan Ambs. High urinary thromboxane B2 associates with lethal prostate cancer in African American men and inversely correlates with aspirin use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 34.

Abstract PO-157: High urinary thromboxane B2 associates with aggressive prostate cancer and inversely correlates with aspirin use

Abstract Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African-American (AA) men potentially contributing to aggressive disease and mortality. Regular use of the anti-inflammatory drug aspirin is associated with decreased risk of advanced stage PC and increased disease-free survival in AA men. The chemopreventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 is an eicosanoid produced by the COX 1 enzyme in platelets. Aspirin inhibits cancer metastasis by inhibiting COX1 activity and thromboxane A2 synthesis. Hence, we assessed the role of thromboxane A2 in the development of lethal PC. Because thromboxane A2 is highly unstable, we measured its corresponding primary metabolite, urinary thromboxane b2 (TXB2), to examine the relationship of thromboxane A2 levels with PC. Method: TXB2 was measured in cases (977) and controls (1023) from the NCI-MD PC Case Control study using a mass-spectrometry-based assay. We estimated odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, with TXB2 levels modeled by quartiles. Multivariable models were adjusted for PC risk factors. Results: We observed an inverse relationship between aspirin use and levels of TXB2 in both cases and controls. For cases who used aspirin, the odds of having TXB2 urinary levels in the highest quartile (Q4) were significantly reduced when compared to non-users (adjusted OR = 0.29 95%CI 0.19-0.4) and this observation remained significant when stratified by race/ethnicity (AA men: OR 0.21 95%CI 0.11-0.38) (EA men: OR 0.34 95%CI 0.19-0.61), indicating significant inhibition of TXB2 formation by aspirin. The adjusted OR for PC was 1.42 (95%CI 1.09-1.85) for men in Q4 compared to Q1 (P trend 0.002). There was an association between TXB2 and PC in AA men (Q4 adjusted OR 1.95 95%CI 1.31-2.91, P trend <0.000) but not EA men (Q4 adjusted OR 1.04 95%CI 0.72-1.49, P trend 0.58), indicating increased thromboxane A2 synthesis in AA men with PC when compared to AA men without the disease. Also, men with Q4 levels of TXB2 were more likely to be diagnosed with metastasis compared to men with Q1 levels of TXB2 (adjusted OR 6.98 95%CI 1.51-32.32, P trend 0.014), indicating more aggressive disease for cases with the highest levels of TXB2. Conclusion: Aspirin use is protective against high levels of urinary TXB2. This is of clinical interest as we report increased urinary TXB2 associates with PC in AA men as well as with more aggressive PC which disproportionally affects AA men. These findings are consistent with our previous findings that aspirin inhibits aggressive disease in AA men and highlights the potential benefit of aspirin as a chemoprotective agent for this population through inhibition of thromboxane A2 synthesis. Citation Format: Maeve Kiely, Ginger Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Michael B. Cook, Clayton Yates, Stefan Ambs. High urinary thromboxane B2 associates with aggressive prostate cancer and inversely correlates with aspirin use [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-157.

Body shape and pants size as surrogate measures of obesity among males in epidemiologic studies.

This study aimed at characterizing anthropometric indicators that can be used as alternatives to measurements for assessing overall obesity over adulthood and abdominal obesity among men. We used data from a population-based case-control study of prostate cancer conducted in Montreal, Canada in 2005-2012. It included men aged ≤ 75 years, 1872 of which were newly diagnosed with prostate cancer, and 1918 others randomly selected from the electoral list. In-person interviews elicited reports of height as well as of weight, pants size and Stunkard's silhouette at 5 time points over adulthood, i.e., for the ages of 20, 40, 50 and 60 years, if applicable, and at the time of interview. Waist and hip circumferences were measured by interviewers following a validated protocol. Analyses were conducted on the overall sample of 3790 subjects, after having confirmed that results did not differ according to disease status. Stunkard's silhouette scale proved to be an easy-to-administer tool that reflects well reported body mass index, either recently or decades in the past among adult males. It was discriminatory enough to classify individuals according to commonly-used obesity categories. We observed that a model including age, reported pants size, silhouette and weight can reasonably predict current abdominal obesity. In conclusion, alternative anthropometric indicators can serve as valuable means to assess overall and abdominal obesity when measurements cannot be envisaged in the context of epidemiological studies.

Abstract C076: Effect of obesity and inflammation on prostate cancer disease risk and mortality among African and European American men

Abstract Prostate cancer (PCa) is a major cause of cancer death in U.S. men. Age-adjusted mortality rates for men of African ancestry (40.8 per 100,000) are more than twice that of men of European ancestry (18.2 per 100,000). Men of African ancestry are more likely to have advanced stage cancer at diagnosis and lower prostate cancer survival rates relative to men of European ancestry of similar age and stage at diagnosis. Risk factors that may explain this survival disparity remain poorly understood. Obesity, a major risk factor for cancer development, aggressiveness and progression, disproportionately affects US men of African ancestry. Age-adjusted prevalence of obesity are higher among men of African ancestry (38.0%) compared to men of European ancestry (34.7%). While it has been previously suggested that obesity may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer mortality remains unclear, with studies showing mixed or null results in men of African ancestry. Less is known about the underlying biological mechanisms that may contribute to the racial differences observed in the link between obesity and prostate cancer. We previously reported an obesity paradox among African-American men in the NCI-Maryland Prostate Cancer-Case Control Study, with overweight and obese men having a lower risk of being diagnosed with the disease. Here, using Cox proportional hazard regression modeling, we estimated the risk of a PCa mortality for the 976 cases in the study. Our primary analysis suggests an obesity paradox, where obesity may protect against disease mortality among the African-American men. In subsequent analyses, we will examine the role of immune and inflammation markers in mediating or moderating the observed relationship of obesity with PCa in these men. Citation Format: Margaret S Pichardo, Tsion Minas, Wei Tang, Tiffany Dorsey, Michael Cook, Stefan Ambs. Effect of obesity and inflammation on prostate cancer disease risk and mortality among African and European American men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C076.

Abstract 625: Association between obesity and prostate cancer disease risk and mortality among African American men

Abstract Prostate cancer (PCa) is a major cause of cancer death in U.S. men. Age-adjusted mortality rates for men of African ancestry (40.8 per 100,000) are more than twice that of men of European ancestry (18.2 per 100,000). Men of African ancestry are more likely to have advanced stage cancer at diagnosis and lower prostate cancer survival rates relative to men of European ancestry of similar age and stage at diagnosis. Risk factors that may explain this survival disparity remain poorly understood. Obesity, a major risk factor for cancer development, aggressiveness and progression, disproportionately affects US men of African ancestry. Age-adjusted prevalence of obesity are higher among men of African ancestry (38.0%) compared to men of European ancestry (34.7%). While it has been previously suggested that obesity may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer mortality remains unclear, with studies showing mixed or null results in men of African ancestry. Less is known about the underlying biological mechanisms that may contribute to the racial differences observed in the link between obesity and prostate cancer. We previously reported an obesity paradox among African-American men in the NCI-Maryland Prostate Cancer-Case Control Study, with overweight and obese men having a lower risk of being diagnosed with the disease. Here, using Cox proportional hazard regression modeling, we estimated the risk of a PCa mortality for the 976 cases in the study. Our primary analysis suggests an obesity paradox, where obesity may protect against disease mortality among the African-American men. In subsequent analyses, we will examine the role of immune and inflammation markers in mediating or moderating the observed relationship of obesity with PCa in these men. Citation Format: Margaret Saira Pichardo, Tsion Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Association between obesity and prostate cancer disease risk and mortality among African American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 625.

Characterizing Short-Term Jobs in a Population-Based Study.

Work histories generally cover all jobs held for ≥1 year. However, it may be time and cost prohibitive to conduct a detailed exposure assessment for each such job. While disregarding short-term jobs can reduce the assessment burden, this can be problematic if those jobs contribute important exposure information towards understanding disease aetiology. To characterize short-term jobs, defined as lasting more than 1 year, but less than 2 years, in a population-based study conducted in Montreal, Canada. In 2005-2012, we collected work histories for some 4000 participants in a case-control study of prostate cancer. Overall, subjects had held 19 462 paid jobs lasting ≥1 year, including 3655 short-term jobs. Using information from interviews and from the Canadian Classification and Dictionary of Occupations, we characterized short-term jobs and compared them to jobs held ≥2 years. Short-term jobs represented <4% of subjects' work years on average. Forty-five per cent of subjects had at least one short-term job; of these, 49% had one, 24% had two, and 27% had at least three. Half of all short-term jobs had been held before the age of 24. Short-term jobs entailed more often exposure to fumes, odours, dust, and/or poor ventilation than longer jobs (17 versus 13%), as well as outdoor work (10 versus 5%) and heavy physical activity (16 versus 12%). Short-term jobs occurred often in early careers and more frequently entailed potentially hazardous exposures than longer-held jobs. However, as they represented a small proportion of work years, excluding them should have a marginal impact on lifetime exposure assessment.

Usual adult occupation and risk of prostate cancer in West African men: the Ghana Prostate Study

ObjectivesEstablished prostate cancer (PCa) risk factors include age, family history of PCa and African ancestry. Studies, mostly among highly screened, predominantly European ancestral populations, suggest that employment in certain occupations...

Association of Anthropometric Measures with Prostate Cancer among African American Men in the NCI-Maryland Prostate Cancer Case-Control Study.

Background: Obesity is a cancer risk factor. Although it does not increase the risk of localized prostate cancer, it raises the risk of the aggressive disease in men of European ancestry. Few studies investigated obesity as a prostate cancer risk factor in men of African ancestry. Findings from those studies were heterogeneous, but some reported an association of excess body fatness with aggressive disease.Methods: We examined the relationship of body mass index (BMI), waist circumference, and waist-hip ratio with prostate cancer in African American (AA) and European American (EA) men in the NCI-Maryland Prostate Cancer Case-Control Study consisting of 798 men with incident prostate cancer (402 AA and 496 EA) and 1,008 population-based controls (474 AA and 534 EA). BMI was self-reported. Waist circumference and waist-hip ratio were calculated from measurements at enrollment.Results: A high BMI either at enrollment or years prior to it was associated with a decreased risk of prostate cancer in AA men. In contrast, an elevated BMI tended to increase the disease risk in EA men. Waist circumference was inversely associated with prostate cancer in both AA and EA men, whereas a high waist-hip ratio did not associate with prostate cancer in AA men but tended to be associated with advanced/aggressive disease in EA men.Conclusions: Our findings reveal an obesity paradox among AA men in this study population, where a high BMI and waist circumference associated with a decreased disease risk.Impact: Our observations expand the knowledge of how obesity may affect prostate cancer risks in AAs. Cancer Epidemiol Biomarkers Prev; 27(8); 936-44. ©2018 AACR.

Abstract 5283: Association between body mass index and prostate cancer among African American men

Abstract Prostate cancer (PCa) is a leading cause of cancer death in US men. Yet, the etiology of prostate cancer remains poorly understood, with only older age, African ancestry, family history of the disease, and multiple germline genetic variations being established disease risk factors. Prostate cancer occurs more often in African-American (AA) men and Caribbean men of African descent than in men of other race/ethnicities. While it has been previously suggested that obesity (measured using body mass index [BMI, kg/m2]) may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer risk, using race as a predictor, has not been fully explored. Using multivariable logistic regression, we estimated the risk of total PCa for 976 cases and 1,032 age-matched controls, with equal proportions of European-American (EA) and AA men. Among men in the NCI Maryland Prostate Cancer Case-Control Study, BMI was inversely associated with disease outcomes in AA men, but not among EA men. Consistent with previous literature, BMI in EA men was shown to be positively associated with overall prostate cancer risk. Our findings suggest an obesity paradox, where obesity may protect against incidence of PCa among AA men. Studies are needed to elucidate the underlying mechanisms responsible for the differential effects of obesity in AA and EA men with prostate cancer. Citation Format: Margaret S. Pichardo, Cheryl J. Smith, Wei Tang, Tiffany Dorsey, Stefan Ambs. Association between body mass index and prostate cancer among African American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5283. doi:10.1158/1538-7445.AM2017-5283

Aspirin Use Reduces the Risk of Aggressive Prostate Cancer and Disease Recurrence in African-American Men.

Background: Men of African descent experience a disproportionately high prostate cancer mortality. Intratumoral inflammation was found to be associated with aggressive prostate cancer. We and others have shown that prostate tumors in African-American (AA) patients harbor a distinct immune and inflammation signature when compared with European-American (EA) patients. These observations suggest that inflammation could be a driver of aggressive disease in men of African descent, leading to the hypothesis that an anti-inflammatory drug like aspirin could prevent disease progression.Methods: We examined the relationship between aspirin use and prostate cancer in the NCI-Maryland Prostate Cancer Case-Control Study consisting of 823 men with incident prostate cancer (422 AA and 401 EA) and 1,034 population-based men without the disease diagnosis (486 AA and 548 EA).Results: We observed a significant inverse association between regular aspirin use and prostate cancer among AA men. Stratification of AA patients by disease stage showed that daily and long-term (>3 years) aspirin use significantly decreased the risk of advanced disease [adjusted ORs for T3/T4 disease: 0.35, 95% confidence interval (CI), 0.17-0.73; and 0.22, 95% CI, 0.08-0.60, respectively], but not early-stage disease (T1/T2). Regular aspirin use also reduced disease recurrence in AA men.Conclusions: Regular aspirin use is associated with a decreased risk of advanced stage prostate cancer and increased disease-free survival in AA men.Impact: Regular aspirin use before and after a prostate cancer diagnosis may prevent the development of aggressive disease in AA men who are at risk of a lethal malignancy. Cancer Epidemiol Biomarkers Prev; 26(6); 845-53. ©2017 AACR.

Highlights of This Issue

Toth and colleagues used a subsets (ASSET) meta-analytic approach, to investigate associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas. Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. Variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, ER-negative breast, overall prostate, overall and serous ovarian cancer. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, overall and aggressive prostate cancer risk. Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology.Lee and colleagues investigated the relationship between nut consumption and lung cancer in the Environment And Genetics in Lung cancer Etiology (EAGLE) study and the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study. The study found higher frequency of intake of nut consumption was inversely associated with overall lung cancer risk and associations were independent of cigarette smoking and other known risk factors.Li-Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are ofta model en used in clinical counseling. Existing LFS criteria have limitations. Peng and colleagues present a Mendelian model, LFSPRO, which estimates TP53 mutation probability through the Elston-Stewart algorithm, and consequently estimates future risk of cancer. LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center. LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS.Men of African descent experience a disproportionately high prostate cancer mortality and studies have shown that prostate tumors in African-American (AA) patients harbor a distinct immune and inflammation signature when compared with European-American (EA) patients. Smith and colleagues examined the relationship between aspirin use and prostate cancer in the NCI-Maryland Prostate Cancer Case-Control Study consisting of men with incident prostate cancer and population-based men without the disease diagnosis. The authors report a significant inverse association between regular aspirin use and prostate cancer among AA men. Regular aspirin use before and after a prostate cancer diagnosis may prevent the development of aggressive disease in AA men who are at risk of a lethal malignancy.

Abstract 4287: Serum metabolomic profiling of prostate cancer risk in the PLCO Cancer Screening Trial

Abstract Background: Two recent studies conducted in one cohort (the ATBC Study) identified serum metabolites related to aggressive prostate cancer up to 20 years prior to diagnosis. Lipid and energy metabolites were significantly lower in cases than in controls, including glycerophospholipids, fatty acids, inositol-1-phosphate, alpha-ketoglutarate, and citrate. The present metabolomics investigation aimed to re-examine those associations in another cohort. Methods: A nested case-control study of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) Trial cohort was conducted based on 380 cases (298 stage 3-4 or Gleason sum 8+; “aggressive disease”), and 380 controls matched on age, race, study center, and date of baseline blood collection (samples were collected between 7am and 4pm). Median time from serum collection to prostate cancer diagnosis was 10.0 years (range, 4.4-17.0), and the majority of cases included in this study were diagnosed after the end of the PLCO screenings. Sera were analyzed on a high resolution accurate mass (HRAM) platform of ultrahigh performance liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography/mass spectroscopy (GC-MS) (Metabolon, Inc.) that identified 722 metabolites. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of risk associated with a one standard deviation (1-SD) increment in metabolite concentration. Results: Of the 27 metabolites associated with prostate cancer at p&amp;lt;0.05, 12 were amino acids or dipeptides, and amino acids as a metabolite class were somewhat overrepresented among the top signals for stage 3-4 but not overall prostate cancer (p = 0.003 and p = 0.08, respectively). Pyroglutamine, gamma-glutamylphenylalanine, phenylpyruvate, N-acetylcitrulline, and stearoylcarnitine yielded the strongest metabolite prostate cancer risk signals (1-SD increment ORs 0.78, 0.76, 0.73, 0.80, and 1.25, respectively; 0.001 &amp;lt; p &amp;lt; 0.006). Findings were similar for aggressive disease. We did not replicate our earlier findings of inverse associations with aggressive prostate cancer for the energy metabolites alpha-ketoglutarate or citrate in the present study (ORs 1.17 and 1.16 (p = 0.10 and 0.03), respectively), or the positive associations for trimethylamine-N-oxide (TMAO) or thyroxin (ORs 0.88 and 0.84 (p = 0.13 and 0.04), respectively). Conclusions: In this prospective case-control analysis of serum collected throughout the day without regard to fasting status, we did not find strong prostate cancer associations for lipid or energy metabolites. Rather, amino acids appeared overrepresented in relation to prostate cancer risk. Whether the baseline and subsequent prostate cancer screening with PSA and digital rectal exams or the non-fasting status of the parent cohort contributed to the findings should be examined in other similar studies. Citation Format: Alison M. Mondul, Stella Koutros, Stephanie J. Weinstein, Sonja I. Berndt, Demetrius Albanes. Serum metabolomic profiling of prostate cancer risk in the PLCO Cancer Screening Trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4287.

Abstract 1776: Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study

Abstract Prostate cancer is a leading cause of cancer death in US men. Yet, the etiology of prostate cancer remains poorly understood, with only older age, African ancestry, family history of the disease, and multiple germline genetic variations being established disease risk factors. Prostate cancer occurs more often in African-American men and Caribbean men of African descent than in men of other race/ethnicities. The causes of these racial and ethnic differences are multifactorial, but it has been proposed that differences in tumor biology contribute to the health disparity associated with prostate cancer. Previously, our laboratory discovered immunobiology differences between African-American and European-American men where genes involved in the inflammatory response tended to be up-regulated in tumors of African American patients. Accumulating evidence suggests that inflammation may be involved in prostate carcinogenesis. Given these observations, we hypothesized that inflammation may contribute to prostate cancer risk and the survival health disparity observed between African-Americans and European-Americans. To this end, we conducted a case-control study in the greater Baltimore area where we recruited 1000 cases and 1000 controls composed of equal populations of African-American and European-American men. In our survey, we asked about non-steroidal anti-inflammatory drugs (NSAIDs) use categorized into aspirin, Tylenol, and other pain relievers that neither contain Tylenol nor aspirin. We found a significant association between aspirin use and prostate cancer risk—where aspirin use decreased the risk of prostate cancer. Strikingly, the decreased prostate cancer risk as a result of aspirin use was most profound in African-American men. We were also able to measure the levels of C-reactive protein, a marker for inflammation, to further evaluate the relationship between aspirin use, inflammation, and prostate cancer risk. Indeed, we did observe a decrease in C-reactive protein in patients who took aspirin. Interestingly, overall levels in healthy controls and prostate cases were higher in African-American subjects and patients when compared to European-Americans. Although aspirin use decreased C-reactive protein levels in African-American and European-American cases, African-Americans had significantly higher levels of C-reactive protein. The robust association between aspirin consumption and prostate cancer risk suggests that inflammation might be a driver in prostate cancer of African-American men. Additionally, the increased levels of C-reactive protein in African-American controls and cases might contribute to the excessive disease risk and mortality among these men. Citation Format: Cheryl J. Smith, Symone Jordan, Tiffany H. Dorsey, Dean Mann, Chris A. Loffredo, Elise Bowman, Wei Tang, Stefan Ambs. Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1776.

Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence.

Metabolite profiling is being increasing employed in the study of prostate cancer as a means of identifying predictive, diagnostic, and prognostic biomarkers. This review provides a summary and critique of the current literature. Thirty-three human case-control studies of prostate cancer exploring disease prediction, diagnosis, progression, or treatment response were identified. All but one demonstrated the ability of metabolite profiling to distinguish cancer from benign, tumor aggressiveness, cases who recurred, and those who responded well to therapy. In the subset of studies where biomarker discriminatory ability was quantified, high AUCs were reported that would potentially outperform the current gold standards in diagnosis, prognosis, and disease recurrence, including PSA testing. There were substantial similarities between the metabolites and the associated pathways reported as significant by independent studies, and important roles for abnormal cell growth, intensive cell proliferation, and dysregulation of lipid metabolism were highlighted. The weight of the evidence therefore suggests metabolic alterations specific to prostate carcinogenesis and progression that may represent potential metabolic biomarkers. However, replication and validation of the most promising biomarkers is currently lacking and a number of outstanding methodologic issues remain to be addressed to maximize the utility of metabolomics in the study of prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 887-906. ©2016 AACR.

Abstract A07: Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer

Abstract We previously reported results from a case-control study nested in a large hospital-based cohort of men identified over a 12-year period (1990-2002) that gene promoter hypermethylation in histopathologically benign prostate specimens is a marker of prostate cancer risk (Tang et al. J Urol 2013). Whether methylation in pre-diagnostic benign prostate tissue can also predict subsequent disease prognosis has not been studied. Therefore, we estimated hazard ratios (HRs) for biochemical recurrence (BCR), defined as two successive prostate-specific antigen increases after definitive treatment, associated with methylation status of the two genes we found associated with prostate cancer risk: retinoic acid receptor-β (RARB) and adenomatosis polyposis coli (APC). Follow-up data were from a subset of the cases (n=394) that were part of our aforementioned nested prostate cancer case-control study of gene promoter methylation status of five genes measured in pre-diagnostic benign biopsy specimens. Overall, after adjusting for known clinical risk factors for prostate cancer progression (advanced grade, advanced stage, high prostate-specific antigen (PSA)), neither methylation of the APC or the RARB genes was associated with a significantly increased risk of BCR, but risk associated with RARB methylation was elevated (HR=1.30; 95% CI= 0.93-1.83). This risk was higher in Whites (HR=1.44; 95% CI= 0.92-2.25) compared with African Americans (HR=1.22; 95% CI= 0.71-2.12), but differences by race were not significant. In additional stratified analyses, we found that while associations with APC methylation did not differ between strata, RARB methylation showed significantly increased risk of BCR in specific substrata; specifically men with high PSA at time of diagnosis (HR=1.73; 95% CI=1.13–2.64) and men in whom methylation did not occur in the four other genes under study (HR=1.82; 95% CI=1.14–2.93). In conclusion, we show for the first time that methylation events occurring before onset of prostate cancer may predict the course of subsequent cancer in defined patient groups. These findings may have important clinical decision making implications in terms of both identifying aggressive prostate cancer at its earliest stages and also avoiding unnecessary additional diagnostic biopsies. Citation Format: Benjamin Rybicki, Michelle Jankowski, Kieu Do, Dhananjay Chitale, Sheri Trudeau, Andrew Rundle, Steven Belinsky, Deliang Tang. Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A07.

Association between plasma fluorescent oxidation products and erectile dysfunction: A prospective study.

BackgroundExisting epidemiological studies of the association between oxidative stress and erectile dysfunction (ED) are sparse and inconclusive, which is likely due to cross-sectional design and small sample size. Therefore, we investigated the association between biomarkers of oxidative stress and ED in prospective setting among a relatively large sample size of men.MethodsWe conducted the prospective study among 917 men ages between 47 and 80 years at the time of blood draw, which is a part of nested prospective case–control study of prostate cancer in the Health Professionals Follow-up Study. Plasma fluorescent oxidation products (FlOPs), a global biomarker for oxidative stress, were measured at three excitation/emission wavelengths (360/420 nm named as FlOP_360; 320/420 nm named as FlOP_320 and 400/475 nm named as FlOP_400).ResultsApproximately 35 % of men developed ED during follow-up. We did not find an independent association between FlOP_360, FlOP_320, FlOP_400 and risk of ED in the multivariable adjusted model (Tertile 3 vs. tertile 1: odds ratio [OR] = 0.90, 95 % confidence interval [CI] = 0.61-1.34, Ptrend = 0.54 for FlOP_360; OR = 0.73, 95 % CI = 0.49-1.07, Ptrend = 0.27 for FlOP_320; and OR = 0.98, 95 % CI = 0.66-1.45, Ptrend = 0.72 for FlOP_400). Further analysis of the association between FlOPs and ED in the fasting samples or controls only (free of prostate cancer incidence) did not change the results appreciably.ConclusionsPlasma FlOPs were not associated with the risk of ED, suggesting oxidative stress may not be an independent risk factor for ED.Electronic supplementary materialThe online version of this article (doi:10.1186/s12894-015-0083-9) contains supplementary material, which is available to authorized users.

Tobacco smoking, polymorphisms in carcinogen metabolism enzyme genes, and risk of localized and advanced prostate cancer: results from the California Collaborative Prostate Cancer Study.

The relationship between tobacco smoking and prostate cancer (PCa) remains inconclusive. This study examined the association between tobacco smoking and PCa risk taking into account polymorphisms in carcinogen metabolism enzyme genes as possible effect modifiers (9 polymorphisms and 1 predicted phenotype from metabolism enzyme genes). The study included cases (n = 761 localized; n = 1199 advanced) and controls (n = 1139) from the multiethnic California Collaborative Case–Control Study of Prostate Cancer. Multivariable conditional logistic regression was performed to evaluate the association between tobacco smoking variables and risk of localized and advanced PCa risk. Being a former smoker, regardless of time of quit smoking, was associated with an increased risk of localized PCa (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 1.0–1.6). Among non-Hispanic Whites, ever smoking was associated with an increased risk of localized PCa (OR = 1.5; 95% CI = 1.1–2.1), whereas current smoking was associated with risk of advanced PCa (OR = 1.4; 95% CI = 1.0–1.9). However, no associations were observed between smoking intensity, duration or pack-year variables, and advanced PCa. No statistically significant trends were seen among Hispanics or African-Americans. The relationship between smoking status and PCa risk was modified by the CYP1A2 rs7662551 polymorphism (P-interaction = 0.008). In conclusion, tobacco smoking was associated with risk of PCa, primarily localized disease among non-Hispanic Whites. This association was modified by a genetic variant in CYP1A2, thus supporting a role for tobacco carcinogens in PCa risk.

Use of oral anticoagulants and risk of prostate cancer: a population-based case-control study in Montreal, Canada.

A few recent epidemiological observations suggest that anticoagulant medications may protect against prostate cancer development. Most studies have been small or subjected to methodological issues, including potential confounding. We provide here new evidence on this association in the context of a population-based case-control study of prostate cancer conducted in Montreal, Canada. Cases were 1,588 men with incident prostate cancer, aged ≤75years, diagnosed across French hospitals in the Montreal area between 2005 and 2009. Concurrently, 1,618 population controls from the same residential area and age distribution (±5years) were randomly selected from the electoral list of French-speaking men. In-person interviews elicited information on socio-demographic, lifestyle and environmental factors, along with a detailed medical history. Unconditional logistic regression was used to assess the association between lifetime use of anticoagulants and prostate cancer risk. 102 subjects (2.6% of cases and 3.7% of controls) reported a history of oral anticoagulant therapy. After controlling for age, ancestry, education, family history of prostate cancer, prostate cancer screening frequency, diabetes, body mass index and statin use, ever use of oral anticoagulants showed a weak inverse, non-statistically significant association with prostate cancer (odds ratio 0.76, 95% confidence interval 0.50-1.16). Similar results were observed in analyses considering duration of use or indication for use, restricted to subjects recently screened or stratified by cancer aggressiveness. Our findings provide weak support for a protective effect of oral anticoagulant therapy against prostate cancer. Further confirmation is required, especially in light of potential bleeding complications associated with anticoagulants.