Joanne L. Watters

Cigarette Smoking and Prostate Cancer in a Prospective US Cohort Study

Smoking is an important risk factor for many cancers, yet the relationship between smoking and prostate cancer remains uncertain. We investigated whether smoking affected the risk of prostate cancers within a large prospective cohort study of dietary and environmental cancer risk factors among men ages 50 to 71 upon enrollment in 1995-1996 (n = 283,312). Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (95% CI) were adjusted for age, race, education, height, body mass index, physical activity, family history of prostate cancer, diabetes, self-reported health status, prostate-specific antigen testing, digital rectal exam, total energy, α-tocopherol, calcium, α-linolenic acid, selenium, red meat, fish, and tomato intake. There were 14,810 nonadvanced and 1,830 advanced incident prostate cancers identified through 2003, and 394 men died of their disease through 2005. Current smokers had a decreased risk of nonadvanced prostate cancer (HR, 0.82; 95% CI, 0.77-0.88), but an increased risk of fatal prostate cancer (HR, 1.69; 95% CI, 1.25-2.27). Former smoking was also associated with decreased risk of nonadvanced prostate cancers (HR, 0.89; 95% CI, 0.86-0.92), but not fatal prostate cancers (HR, 1.03; 95% CI, 0.83-1.27). There was no apparent association between smoking and advanced prostate cancer. A number of biologically plausible mechanisms could explain these results, including the direct effects of carcinogens in tobacco smoke and the resulting changes in sex hormone or growth factor profiles. These findings suggest that current and former smokers may be at decreased risk of being diagnosed with prostate cancer and current smokers are at an increased risk of dying from prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2427–35)

Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium

Background: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A1 versus A2 variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A1 allele would confer greater risk than A2 allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. Methods: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. Results: An increased risk was observed in participants with A1 but not A2 alleles. Compared with subjects with genotype O/O, genotypes A2/O, A2/A1, A1/O, and A1/A1 had ORs of 0.96 (95% CI, 0.72–1.26), 1.46 (95% CI, 0.98–2.17), 1.48 (95% CI, 1.23–1.78), and 1.71 (95% CI, 1.18–2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A1, and A2 were 1.00 (95% CI, 0.87–1.14), 1.38 (95% CI, 1.20–1.58), and 0.96 (95% CI, 0.77–1.20); P, O01 versus O02 = 0.94, A1 versus A2 = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). Conclusions: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. Impact: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34. Cancer Epidemiol Biomarkers Prev; 19(12); 3140–9. ©2010 AACR.

Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium

Background: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A1 versus A2 variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A1 allele would confer greater risk than A2 allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. Methods: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. Results: An increased risk was observed in participants with A1 but not A2 alleles. Compared with subjects with genotype O/O, genotypes A2/O, A2/A1, A1/O, and A1/A1 had ORs of 0.96 (95% CI, 0.72–1.26), 1.46 (95% CI, 0.98–2.17), 1.48 (95% CI, 1.23–1.78), and 1.71 (95% CI, 1.18–2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A1, and A2 were 1.00 (95% CI, 0.87–1.14), 1.38 (95% CI, 1.20–1.58), and 0.96 (95% CI, 0.77–1.20); P, O01 versus O02 = 0.94, A1 versus A2 = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). Conclusions: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. Impact: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34. Cancer Epidemiol Biomarkers Prev; 19(12); 3140–9. ©2010 AACR.

Associations between α-Tocopherol, β-Carotene, and Retinol and Prostate Cancer Survival

Previous studies suggest that carotenoids and tocopherols (vitamin E compounds) may be inversely associated with prostate cancer risk, yet little is known about how they affect prostate cancer progression and survival. We investigated whether serum alpha-tocopherol, beta-carotene, and retinol concentrations, or the alpha-tocopherol and beta-carotene trial supplementation, affected survival of men diagnosed with prostate cancer during the alpha-Tocopherol, beta-Carotene Cancer Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial testing the effects of beta-carotene and alpha-tocopherol supplements on cancer incidence in adult male smokers in southwestern Finland (n = 29,133). Prostate cancer survival was examined using the Kaplan-Meier method with deaths from other causes treated as censoring, and using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CI) adjusted for family history of prostate cancer, age at randomization, benign prostatic hyperplasia, age and stage at diagnosis, height, body mass index, and serum cholesterol. As of April 2005, 1,891 men were diagnosed with prostate cancer and 395 died of their disease. Higher serum alpha-tocopherol at baseline was associated with improved prostate cancer survival (HR, 0.67; 95% CI, 0.45-1.00), especially among cases who had received the alpha-tocopherol intervention of the trial and who were in the highest quintile of alpha-tocopherol at baseline (HR, 0.51; 95% CI, 0.20-0.90) or at the 3-year follow-up measurement (HR, 0.26; 95% CI, 0.09-0.71). Serum beta-carotene, serum retinol, and supplemental beta-carotene had no apparent effects on survival. These findings suggest that higher alpha-tocopherol (and not beta-carotene or retinol) status increases overall prostate cancer survival. Further investigations, possibly including randomized studies, are needed to confirm this observation.

Alcoholic Beverages and Prostate Cancer in a Prospective US Cohort Study

Despite numerous investigations, the correlation between alcohol consumption and prostate cancer risk remains uncertain. This report investigated the association between alcohol use and prostate cancer risk in a prospective cohort study of 294,707 US men aged 50-71 years in 1995-1996. Cox proportional hazards regression models with hazard ratios and 95% confidence intervals were adjusted for characteristics including age, race, body mass index, physical activity, and family history of prostate cancer, as well as testing for prostate-specific antigen and a digital rectal examination. There were 15,327 nonadvanced and 1,900 advanced prostate cancers identified through 2003 and 514 fatal cases through 2005. Risk of nonadvanced prostate cancer was 25% higher for men consuming ≥6 drinks daily (hazard ratio = 1.25, 95% confidence interval: 1.13, 1.37), 19% higher for men consuming 3-<6 drinks daily, and 6% higher for men consuming up to 3 drinks daily, compared with nondrinkers. The association between alcohol consumption and nonadvanced prostate cancer risk did not differ appreciably by age, family history of prostate cancer, smoking status, body mass index, or self-reported prostate-specific antigen testing and digital rectal examination (the latter available for >60% of respondents). The authors observed no association between alcohol intake and advanced prostate cancer and an inverse association with fatal prostate cancer among heavy drinkers. These findings suggest that higher alcohol consumption modestly increases nonadvanced prostate cancer risk.

Serum Retinol and Risk of Prostate Cancer

Greater exposure to retinol (vitamin A) may prevent prostate cancer, although under some conditions it could promote cell growth and de-differentiation. The authors prospectively examined prostate cancer risk and serum retinol levels, measured by using high-performance liquid chromatography, at baseline (n = 29,104) and after 3 years (n = 22,843) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041) and aggressive (n = 461) prostate cancer by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years. Men with higher retinol concentrations at baseline were more likely to develop prostate cancer (quintile 5 vs. quintile 1 hazard ratio = 1.19, 95% confidence interval: 1.03, 1.36; P(trend) = 0.009). The results were similar for aggressive disease. Joint categorization based on baseline and 3-year retinol levels showed that men who were in the highest quintile at both time points had the greatest increased risk (baseline/3-year quintile 5/quintile 5 vs. quintile 1/quintile 1 hazard ratio = 1.31, 95% confidence interval: 1.08, 1.59). In this largest study to date of vitamin A status and subsequent risk of prostate cancer, higher serum retinol was associated with elevated risk, with sustained high exposure conferring the greatest risk. Future studies may clarify the underlying biologic mechanisms of the retinol-prostate cancer association.

Correlates of antioxidant nutrients and oxidative DNA damage differ by race in a cross-sectional study of healthy African American and white adults

Although antioxidant nutrients and oxidative DNA damage have been associated with carcinogenesis, few studies have investigated the factors that influence antioxidant intake and oxidative DNA damage in racially diverse populations. Demographic, behavioral, and diet-related psychosocial correlates of plasma antioxidant (carotenoids, vitamin C, and vitamin E) concentrations and oxidative DNA damage were examined using data from a cross-sectional study of 147 generally healthy, nonsmoking African American and white adults in North Carolina, aged 20 to 45 years. All participants completed self-administered demographic, diet, and health questionnaires and provided semifasting (> or = 6 hours) blood samples. Multivariate regression analyses were computed separately for each race to determine associations between the potential correlates with plasma antioxidant concentrations and oxidative DNA damage, separately. Our findings suggest appreciable differences by race. Only a few factors (age, supplement use, and several psychosocial factors) were associated with antioxidant concentrations in African Americans, whereas these and additional factors, including physical activity, waist circumference, and passive smoke exposure, were associated with antioxidant concentrations in whites. For oxidative DNA damage, passive smoke exposure was significantly associated with oxidative DNA damage in African Americans, and age and alcohol were significant in whites. In addition, the regression models generally explained more of the variance in plasma antioxidant concentrations and oxidative DNA damage in whites than in African Americans. Considering the salient correlates differed by race, this work has important implications for the design and implementation of future research studies investigating antioxidant nutrients and/or oxidative stress, especially those in racially diverse populations.

Abstract 2821: Dietary lycopene and prostate cancer risk in the NIH-AARP Diet and Health Study

In the U.S., tomatoes and tomato products contribute almost all dietary intake of lycopene, a carotenoid with antioxidant properties. Some studies have shown reduced prostate cancer risk with diets high in lycopene or tomato-rich foods (e.g., pizza), yet others have not. Despite numerous investigations, there is no consensus concerning the relationship between lycopene and prostate cancer risk. We examined the relation between dietary lycopene and risk of prostate cancer within the National Institutes of Health (NIH)-AARP Diet and Health Study, a large prospective cohort investigation of dietary and environmental cancer risk factors among men aged 50-71 upon enrollment in 1995-1996 (n=292,482). Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (95% CI) were adjusted for age, race, education, height, body mass index, physical activity, family history of prostate cancer, diabetes, prostate-specific antigen testing, digital rectal examination, total energy, α-tocopherol, calcium, α-linolenic acid, selenium, red meat, and fish. There were 15,229 nonadvanced and 1,889 advanced incident prostate cancers identified through 2003 and 510 fatal prostate cancers through 2005. The median intake of dietary lycopene was 2.5 mg/day in the lowest quintile and 14.9 mg/day in the highest quintile of intake. Total lycopene consumption was associated with a slight reduction in risk of nonadvanced prostate cancer (HR= 0.93, 95% CI: 0.88 − 0.99), but there was no association with advanced or fatal prostate cancers. Similar patterns were observed for total tomato consumption. No individual tomato-rich food affected nonadvanced prostate cancer risk. Pizza was associated with a 15% reduction in advanced prostate cancers (95% CI: 0.72 − 1.00) and a 33% reduction in fatal prostate cancers (95% CI: 0.47 − 0.96), whereas salsa consumption was associated with a 28% increase in advanced prostate cancers (95% CI: 1.10 − 1.48). Considering the overall null association between lycopene intake and advanced prostate cancer, it is possible other constituents in these foods may be affecting cancer risk; alternatively, these results for specific foods may be due to chance. Overall, these data suggest that dietary lycopene may be associated with minimal reductions in nonadvanced prostate cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2821.

Abstract A108: Serum retinol and risk of prostate cancer in the alphatocopherol, beta‐carotene (ATBC) cancer prevention study

Purpose: Retinol (vitamin A) may prevent prostate cancer by promoting cell differentiation and apoptosis, although under some conditions it could stimulate growth and de‐differentiation. We examined serum retinol, measured at baseline and three years, in relation to prostate cancer risk in the ATBC Study. Methods: The ATBC Study is a randomized controlled trial conducted to determine the effects of ‐tocopherol and s‐carotene supplements on cancer incidence. 29,133 Finnish male smokers were recruited from 1985–1988 and were assigned to groups using a 2×2 factorial design: 1) ‐tocopherol, 2) β‐scarotene, 3) both supplements, or 4) placebo. Fasting blood samples were collected at baseline and after 3 years, and as of April 30, 2006, 2,041 prostate cancer cases occurred during 417,532 person‐years. Cox proportional hazards models were used to estimate the relative risk (as hazard ratio, HR) of total and aggressive (n=461) prostate cancer by quintile of baseline and 3‐year serum retinol concentrations, as well as by change in serum retinol. No confounding by factors associated with either prostate cancer or retinol was observed. Results: Men in higher quintiles of baseline retinol were more likely to develop prostate cancer compared with men in the lowest quintile (age‐adjusted HR, 95%CI vs. Q1; Q2: 1.05, 0.91 – 1.21; Q3: 1.06 0.92 – 1.22; Q4: 1.13, 0.98 – 1.30; Q5: 1.19, 1.03 – 1.36; p‐trend = 0.009). The association was similar for aggressive prostate cancer and when the 3‐year retinol was used. Compared to men whose retinol did not differ between baseline and 3 years, men with either higher or lower retinol at follow‐up were at similar risk of prostate cancer. When we jointly categorized men based on quintiles of baseline and 3‐year retinol, we noted that men who were in the highest quintile of retinol at both time points had the greatest increased risk (baseline/3‐year Q5/Q5 vs. Q1/Q1 HR: 1.31 95% CI: 1.08 – 1.59). Other joint categories were also at higher risk, particularly among men who did not receive the trial β‐carotene supplement. Men randomized to the β‐carotene arm had generally higher risk for any baseline/3‐year retinol category compared to men in the no β‐carotene arm, and those whose serum retinol decreased substantially from baseline Q4 or Q5 appeared to have a lower prostate cancer risk (HR, 95% CI vs. Q1/Q1; Q5 to Q1–3: 0.60, 0.35 – 1.03; Q4 to Q1–2: 0.85, 0.54 – 1.33). Conclusion: In this largest study to date of serum retinol and prostate cancer that incorporates retinol measured at two time points three years apart, higher serum concentrations were associated with elevated risk, with sustained high exposure conferring the greatest risk. Distinct patterns of change in serum retinol over time may relate to differing risks of developing prostate cancer. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A108.