Alpha-Tocopherol Beta-Carotene Research Articles

Vitamin E and Mortality in Male Smokers of the ATBC Study: Implications for Nutritional Recommendations.

The Dietary Reference Intakes (DRI)-monograph (USA/Canada) states that the estimated average requirement (EAR) of vitamin E for men and women of any age is 12 mg/day. The EAR value is based on in vitro hemolysis in young males; a surrogate endpoint without any direct validity. The EAR is then extrapolated to females and older males. The validity of the EAR level is therefore questionable. Total mortality is an outcome of direct clinical relevance. Investigating the effect of long-term dietary vitamin E intake level on mortality in a randomized trial is, however, not feasible. Nevertheless, the effect of dietary vitamin E intake can be investigated indirectly from the effects of a fixed-level vitamin E supplement administered to participants on variable levels of dietary vitamin E intake. If vitamin E intake below the EAR is harmful, then vitamin E supplement should be beneficial to those people who have dietary vitamin E intake level below the EAR. The purpose of this study was to analyze the association between dietary vitamin E intake and the effect of 25 mg/day of vitamin E supplement on total mortality in Finnish male smokers aged 50–69 years in the Alpha-Tocopherol-Beta-Carotene (ATBC) Study. The effect of vitamin E supplement was estimated by Cox regression. Among participants who had dietary vitamin C intake of 90 mg/day and above, vitamin E supplement increased mortality by 19% (p = 0.006) in those aged 50–62 years, but decreased mortality by 41% (p = 0.0003) in those aged 66–69 years. No association between vitamin E supplement effect and dietary vitamin E intake was found in these two groups, nor in participants who had dietary vitamin C intake less than 90 mg/day. There is no evidence in any of the analyzed subgroups that there is a difference in the effect of the 25 mg/day vitamin E supplement on males on dietary vitamin E intakes below vs. above the EAR of 12 mg/day. This analysis of the ATBC Study found no support for the ‘estimated average requirement' level of 12 mg/day of vitamin E for older males.Trial registration: ClinicalTrials.gov, identifier: NCT00342992.

The effect of β-carotene on the mortality of male smokers is modified by smoking and by vitamins C and E: evidence against a uniform effect of nutrient

A previous analysis of the Alpha-Tocopherol Beta-Carotene (ATBC) Study on male smokers found that β-carotene supplementation increased the risk of pneumonia 4-fold in those who started smoking at the age of ≥21 years and smoked ≥21 cigarettes/d (a subgroup of 7 % of the study population). The present study hypothesised that β-carotene increases mortality in the same subgroup. The ATBC Study (1985-1993) recruited 29 133 Finnish male smokers (≥5 cigarettes/d) aged 50-69 years. Cox regression models were constructed to estimate the effect of β-carotene supplementation in subgroups. β-Carotene increased mortality (risk ratio 1·56; 95 % CI 1·06, 2·3) in those who started to smoke at ≥21 years and smoked ≥21 cigarettes/d. Within this subgroup, there was strong evidence of further heterogeneity. The effect of β-carotene supplementation was further modified by dietary vitamin C intake, fruit and vegetable intake (P = 0·0004), and by vitamin E supplementation (P = 0·011). Thus, harm from β-carotene was not uniform within the study population. Interactions between β-carotene and vitamins C and E were seen only within a subgroup of 7 % of the ATBC participants, and therefore should not be extrapolated to the general population. Heterogeneity of the β-carotene effect on mortality challenges the validity of previous meta-analyses that have pooled many diverse antioxidants for one single estimate of effect using the assumption that a single estimate equally applies to all antioxidants and all people. Trial registration: ClinicalTrials.gov NCT00342992.

Abstract LB-172: Understanding the mechanism underlying vitamin D and prostate cancer: Exploring telomere length

Abstract Background: In an effort to understand the molecular mechanism behind the association between circulating vitamin D and prostate cancer, we measured relative telomere length and 25(OH)D levels in a cohort of older Finnish men. Methods: Using a nested study design, we examined quantitative PCR measured telomere length, season-adjusted serum 25-hydroxyvitamin D [25(OH)D], and subsequent prostate cancer risk in 1000 men (n=500 cases, 500 matched controls) participating in the extension study of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Trial. Conditional regression models were used to explore mediation and effect modification of telomere length on the relation between serum 25(OH)D and prostate cancer risk. Results: An increased risk of prostate cancer was observed among men with longer (>median) relative telomere length (OR = 1.41, 95% CI: 1.06 to 1.90; continuous: OR = 2.36, 95%CI: 0.96 to 5.83) as well as men with higher 25(OH)D concentrations (OR = 1.67, 95% CI: 1.08 to 2.57 for highest vs. lowest quintile, P-trend = 0.03). No significant association between 25(OH)D levels and telomere length was observed. A suggested joint effect of 25(OH)D and telomere length on prostate cancer risk was observed. Conclusion: Serum 25(OH)D and relative telomere length are independent predictors of prostate cancer risk in this sample of older male Finnish smokers. No evidence of mediation between circulating vitamin D concentrations and telomere length was observed. Future studies are needed to further clarify the underlying biologic mechanisms of the 25(OH)D-prostate cancer association. Citation Format: Jacqueline M. Major, Barry I. Graubard, Stephanie J. Weinstein, Jeeyun Kim, Immaculata De Vivo, Jarmo Virtamo, Sharon A. Savage, Demetrius Albanes. Understanding the mechanism underlying vitamin D and prostate cancer: Exploring telomere length [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 LB-172.

COMT Effects on Vitamin E and Colorectal Cancer, in-vitro and in Two Randomized Trials (P15-005-19)

ObjectivesDespite promising observational data and compelling mechanisms of action, vitamin E has failed to demonstrate evidence of benefit in randomized clinical trials (RCTs). In two large long-term placebo-controlled RCTs, we reported that vitamin E effects on total cancer were modified by genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Here we investigate COMT effects on colorectal cancer (CRC) in the two RCTs and a CRC cell line. MethodsWe analyzed COMT rs4680 association with rates of CRC in the Women’s Health Study (WHS), N = 23,294 and a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC). Cell survival and apoptosis were examined in-vitro in HCT116 cells treated with increasing doses of vitamin E when COMT gene expression was inhibited by silencing RNA (siRNA). ResultsRates of CRC were higher with randomized vitamin E compared to placebo among COMT high-activity val/val homozygotes in ATBC (HR, [CI] = 3.00, [1.48–6.09]), but not WHS (HR, [CI] = 0.99, [0.63–1.57]). Among low-activity met/met homozygotes randomized to vitamin E compared to placebo, rates of CRC were borderline lower in WHS (HR, [CI] = 0.66, [0.44–1.01]), but not in ATBC (HR, [CI] = 0.93, [0.63–1.62]).In cell culture, vitamin E at 3 μg/ml and 10 μg/mL had no effect on cell viability or apoptosis. However, silencing COMT resulted in a modest apoptotic effect that vitamin E enhanced in a dose-dependent manner. Human apoptosis arrays indicated that in the absence of COMT expression, vitamin E induced protein expression related to the intrinsic apoptotic pathway through p53 activation, dysregulation of Bcl-2 family protein expression and down-regulation of IAP family protein expression. ConclusionsDifferential COMT effects on vitamin E and CRC were similar to those previously reported for all invasive cancers, but were only significant for val/val homozygotes. Further, inhibiting COMT in the presence of vitamin E in a CRC in-vitro model, recapitulated the RCT observation that among individuals homozygous for the low-activity allele (met/met) vitamin E tended to reduce invasive cancer and here CRC. Funding SourcesNational Institutes of Health: NCI and NHLBI.

COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials.

Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer. Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided. Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial. Pharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.

Effect of β-Carotene Supplementation on the Risk of Pneumonia Is Heterogeneous in Males: Effect Modification by Cigarette Smoking.

Beta-carotene has been suggested to be a factor for improving the immune system, which implies that it might decrease the risk of infections. We therefore analyzed whether beta-carotene supplementation influenced pneumonia risk in 14,564 Finnish male smokers of the Alpha-Tocopherol Beta-Carotene (ATBC) Study. There were 231 pneumonia cases in the beta-carotene group and 217 cases in the placebo group. Thus, beta-carotene had no effect on the average incidence of pneumonia, RR=1.07 (95% CI: 0.89-1.29). However, cigarette smoking exposure significantly modified the effect. Beta-carotene increased pneumonia risk by RR=4.0 (95% CI: 1.63-10) among 990 participants who started to smoke at the age of ≥21 y and smoked ≥21 cigarettes per day at the study baseline. However, beta-carotene had no influence on pneumonia risk for the remaining participants. We also analyzed the effect of beta-carotene on participants who quit smoking during the ATBC Study. Among 4,290 participants who quit smoking, the 58 pneumonia cases were evenly distributed between the beta-carotene and placebo groups with RR=0.93 (95% CI: 0.55-1.55). Accordingly, no evidence was found that beta-carotene decreased pneumonia risk; instead, it significantly increased the incidence of pneumonia in a subgroup that covered 7% of the study population.

Effects of β-Carotene and Its Cleavage Products in Primary Pneumocyte Type II Cells.

β-Carotene has been shown to increase the risk of developing lung cancer in smokers and asbestos workers in two large scale trails, the Beta-Carotene and Retinol Efficacy Trial (CARET) and the Alpha-Tocopherol Beta-carotene Cancer Prevention Trial (ATBC). Based on this observation, it was proposed that genotoxic oxidative breakdown products may cause this effect. In support of this assumption, increased levels of sister chromatid exchanges, micronuclei, and chromosomal aberrations were found in primary hepatocyte cultures treated with a mixture of cleavage products (CPs) and the major product apo-8′carotenal. However, because these findings cannot directly be transferred to the lung due to the exceptional biotransformation capacity of the liver, potential genotoxic and cytotoxic effects of β-carotene under oxidative stress and its CPs were investigated in primary pneumocyte type II cells. The results indicate that increased concentrations of β-carotene in the presence of the redox cycling quinone dimethoxynaphthoquinone (DMNQ) exhibit a cytotoxic potential, as evidenced by an increase of apoptotic cells and loss of cell density at concentrations > 10 µM. On the other hand, the analysis of micronucleated cells gave no clear picture due to the cytotoxicity related reduction of mitotic cells. Last, although CPs induced significant levels of DNA strand breaks even at concentrations ≥ 1 µM and 5 µM, respectively, β-carotene in the presence of DMNQ did not cause DNA damage. Instead, β-carotene appeared to act as an antioxidant. These findings are in contrast with what was demonstrated for primary hepatocytes and may reflect different sensitivities to and different metabolism of β-carotene in the two cell types.

Suboptimal Serum α-Tocopherol Concentrations Observed among Younger Adults and Those Depending Exclusively upon Food Sources, NHANES 2003-20061-3.

Vitamin E is an essential nutrient for human health, with an established function as a lipid-soluble antioxidant that protects cell membranes from free radical damage. Low vitamin E status has been linked to multiple health outcomes, including total mortality. With vitamin E being identified as a ‘shortfall nutrient’ because >90% of American adults are not consuming recommended amounts of vitamin E, we aimed to determine the prevalence of both clinical vitamin E deficiency (serum α-tocopherol concentration < 12 μmol/L) and failure to meet a criterion of vitamin E adequacy, serum α-tocopherol concentration of 30 μmol/L, based on the Estimated Average Requirement (EAR) and lowest mortality rate in the Alpha-Tocopherol Beta-Carotene (ATBC) study. The most recent nationally-representative cross-sectional data (2003–2006) among non-institutionalized US citizens with available serum concentrations of α-tocopherol from the National Health and Nutrition Examination Survey (NHANES); Centers for Disease Control and Prevention were analyzed. Serum α-tocopherol distributions were compared between those reporting consumption of food without supplement use (FOOD) and food and supplement use (FOOD+DS) by sex, age, and race/ethnicity. Only 1% of the US population is clinically deficient. FOOD consumers have lower average α-tocopherol levels (24.9± 0.2 μmol/L) than FOOD+DS users (33.7 ± 0.3 μmol/L), even when adjusted for total cholesterol. Using a criterion of adequacy of 30 μmol/L, 87% of persons 20-30y and 43% of those 51+y had inadequate vitamin E status (p<0.01). A significant greater prevalence of FOOD compared to FOOD+DS users did not meet the criterion of adequacy which was based on the EAR and low ATBC mortality rate consistently across age, sex, and race/ethnic groups. The prevalence of inadequate vitamin E levels is significantly higher among non-users of dietary supplements. With declining usage of vitamin E supplements, the population should be monitored for changes in vitamin E status and related health outcomes.

Mitochondrial DNA copy number and chronic lymphocytic leukemia/small lymphocytic lymphoma risk in two prospective studies.

Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data. In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI). Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03-4.72; Ptrend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72-5.68; Ptrend: 0.0002). Association was stronger among male smokers (Ptrend: <0.0001) and essentially identical for cases diagnosed <6, >6-8, and >8 years from blood draw (pooled: Pinteraction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association. Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development.

Chemoprevention with Vitamins and Minerals: There's Still A Lot to Learn

The health benefits of adequate intake of vitamins, minerals and a host of other natural products are supported by extensive epidemiological data and have become a mainstay of nutritional counseling. The potential for some of these nutrients to reduce cancer mortality is particularly important for patients whose cancer has metastasized and have poor prognosis. Furthermore, efforts to develop vitamins and minerals as dietary supplements to reduce cancer incidence have been ongoing for decades, yet in recent years there has been a decline in both interest and effort in this area. A major reason for this has been the lack of success of large supplementation trials investigating the efficacy of individual supplements in preventing either the development or progression of a variety of cancer types. The failure to detect benefits has been compounded by data obtained from the same trials indicating that for several of the most promising supplements intake was associated with elevated cancer incidence [1]. For example, two large randomized supplementation trials, the AlphaTocopherol Beta-Carotene Cancer Prevention Study (ATBC) and the Beta–Carotene and Retinol Efficiency Trial (CARET) both reported significant increases in lung cancer incidence and mortality among high risk individuals provided beta-carotene. In the largest prostate cancer prevention trial ever conducted, the randomized Selenium and Vitamin E Chemoprevention Trial (SELECT), approximately 35,000 men over the age of 50 were provided vitamin E, selenium, or both and the incidence and grade of prostate cancers developing over a 7 year period were compared to those in men provided placebo. The results of this study indicated that the risk of prostate cancer was increased by 17% in those provided the vitamin E supplement and in the selenium supplemented group, those men who had the highest baseline selenium status experienced an increased risk of high grade prostate cancer by 91% [2]. In a prospective study of men diagnosed with prostate cancer, use of selenium supplements was associated with a significant increase in prostate cancer-specific mortality [3]. More and more, supplementation studies are revealing what is described as a “U shaped dose-response curve” [4], where a supplement is beneficial when provided to individuals with low baseline levels of that substance, but detrimental when provided to those at adequate or above adequate levels.

Pooled analysis of mitochondrial DNA copy number and lung cancer risk in three prospective studies.

We previously reported that higher levels of mitochondrial DNA copy number (mtDNA CN) were associated with lung cancer risk among male heavy smokers (i.e., ≥20 cigarettes per day) in the Alpha-Tocopherol Beta-Carotene (ATBC) study. Here, we present two additional prospective investigations nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and the Shanghai Women's Health Study (SWHS), and pooled with previously published data from ATBC. All DNA were extracted from peripheral whole blood samples using the phenol-chloroform method, and mtDNA CN was assayed by fluorescence-based qPCR. Multivariate unconditional logistic regression models were used to estimate ORs and 95% confidence intervals for the association of mtDNA CN and lung cancer risk. Overall, mtDNA CN was not associated with lung cancer risk in the PLCO, SWHS, or pooled populations (all P trends > 0.42, P heterogeneity = 0.0001), and mtDNA CN was inversely associated with lung cancer risk among male smokers in PLCO, the opposite direction observed in ATBC. In addition, the mtDNA CN association observed among male heavy smokers in ATBC was the opposite direction in PLCO. mtDNA CN was not consistently associated with lung cancer risk across three prospective study populations from Europe, Asia, and the United States. This pooled study suggests no consistent association between prediagnostic mtDNA CN levels and lung cancer risk across several populations. Cancer Epidemiol Biomarkers Prev; 23(12); 2977-80. ©2014 AACR.

Hepatology Highlights

Hepatology Highlights

Vitamin E status of the U.S. adult population by use of dietary supplements (1041.7)

Vitamin E is essential for human health and achieving an optimal status is associated with beneficial health outcomes. Given that &gt;90% of Americans are not meeting vitamin E intake recommendations, we assessed serum α‐tocopherol (AT) and related these to an optimal serum concentration (30 µmol/L) found to have the lowest mortality in the Alpha‐Tocopherol Beta‐Carotene study. Cross‐sectional AT status data from the 2003‐2006 National Health and Nutrition Examination Survey (NHANES) in adults 蠅20y (excluding pregnant and lactating women) was analyzed. Population (n=7969) mean AT concentrations differed by sex, race/ethnicity, age, and dietary supplement use (p &lt; 0.01). Mean AT concentrations were 29.9, 25.0 and 34.2 µmol/L for the total population, non‐supplement (NS), and supplement (S) users, respectively. S users (49% of subjects) had a lower prevalence (45%) of suboptimal AT concentrations (&lt;30 µmol/L) than NS (81%, p&lt;0.01). In addition to differences (p&lt;0.01) in AT concentrations between S and NS subpopulations by gender and race/ethnicity, a higher proportion of younger than older adults had suboptimal AT concentrations (p&lt;0.01) especially if they were not supplement users: 20‐30y NS (93%) vs S (79%); 31‐50y NS (81%) vs S (54%); 51+y NS (71%) vs S (28%). Despite a low prevalence of overt vitamin E deficiency, many American adults have suboptimal AT status even when supplementing their diet.Grant Funding Source: DSM Nutritional Products LLC

Abstract A58: Serum transforming growth factor-β1 and risk of pancreatic cancer in three prospective cohort studies

Abstract Background: Clinically evident chronic pancreatitis is an established, strong risk factor for pancreatic cancer. A small Japanese cohort study reported that pre-diagnostic serum transforming growth factor-β1 (TGF-β1) concentration, a potential marker of subclinical pancreatic inflammation, was associated with higher risk of pancreatic cancer. Methods: Serum TGF-β1 concentrations were measured in pre-diagnostic samples drawn from 729 pancreatic cancer cases and 907 matched controls from a cohort of Finnish male smokers (the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study) and two cohorts of U.S. men and women, the Cancer Prevention Study-II (CPS-II) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Multivariable-adjusted odds ratios (ORs) were estimated using conditional logistic regression. Results: Overall, high serum TGF-β1 concentration was associated with a marginally statistically significant increase in risk of pancreatic cancer (OR = 1.36, 95% confidence interval (CI), 0.98-1.88 for highest vs. lowest quintile). This association differed significantly by follow-up time (p = 0.02). Serum TGF-β1 concentration was not associated with risk during the first 10 years of follow-up, but was associated with risk during follow-up after 10 years (OR = 2.13, 95% CI 1.23-3.68 for highest vs. lowest quintile). Conclusions: These results suggest that high serum TGF-β1 may be associated with increased risk of pancreatic cancer after a latency period of several years. Further research examining the magnitude and timing of associations between serum TGF-β1 and other potential markers of pancreatic inflammation may be useful in clarifying the role of inflammation in pancreatic carcinogenesis. Citation Format: Eric J. Jacobs, Christina C. Newton, Debra Silverman, Leticia Nogueira, Demetrius Albanes, Satu Månnistö, Rachael Z. Stolzenberg-Solomon. Serum transforming growth factor-β1 and risk of pancreatic cancer in three prospective cohort studies. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A58.

A journey towards reducing colon cancer burden

Adeyinka O Laiyemo speaks to NatashaGalukande, Commissioning Editor: Dr Laiyemo iscurrently an Assistant Professor in the Division of Gastroenterologyat the Howard University College of Medicine(Washington, DC, USA), and is heavily involved in studiesfocusing on racial disparity in colorectal cancers. Hegraduated from the University of Lagos (Nigeria) in1990, before working as a General Medical Officer at twohospitals from 1990–1996. Dr Laiyemo had his medicalinternship, medical residency and gastroenterologyfellowship at Howard University College of Medicine from1998–2006. In 2005 he was a cancer prevention fellow at the National CancerInstitute (MD, USA) and in 2006 he graduated from Johns Hopkins University(MD, USA), majoring in epidemiology and biostatics. In recent years Dr Laiyemohas been part of the National Cancer Institute’s Alpha Tocopherol Beta Carotene(ATBC) Cancer Prevention Trial Study Group, the Polyp Prevention Trial (PPT)Study Group, the Prostate, Lung, Colorectal and Ovarian Cancer ScreeningTrial (PLCO) Colon Subcommittee and the Health Information National TrendsSurvey. Laiyemo is a member of the Howard University Advisory Committeeon Graduate Medical Education, the American Association for Cancer Research,the American College of Physicians, the American College of Gastroenterologyand the Alpha Omega Medical Honor Society. He was recently awarded the‘Minority Scholar in Cancer Research Award’ at the 102nd American Associationfor Cancer Research Meeting in Orlando (FL, USA).

Vitamin E: A dark horse at the crossroad of cancer management

It appears that the story on vitamin E and its role in human health remains incomplete. It is apparent that vitamin E supplementation involves many variables, some of which include its uptake from the intestine, the preference for α-tocopherol, transport by tocopherol specific proteins and lipid transporters and the differential metabolism of different vitamin E isoforms. The fundamental differences within population genetics can have significant implications for the effect that dietary supplementation might have on human health. When evaluating the efficacy of vitamin E prophylactic or therapeutic use in previous and future studies, it is critical to consider dosage to be administered, form of vitamin E and source (such as whether from synthetic or purified from natural sources). Further studies are needed to determine the effects of all vitamin E isoforms on cell growth, tumorigenicity, to clarify its possible use as an adjuvant to existing chemotherapeutics. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study Group and Selenium and Vitamin E Cancer Prevention Trial (SELECT) studies along with the numerous studies of vitamin E should help guide the next chapter of vitamin E research.

A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study

Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.

Iron in Relation to Gastric Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis. Serum iron metrics were not associated with GCC, except for a potential "n"-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a "u"-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations. We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency. Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted.

Abstract 13: Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study.

Abstract Genome-wide association studies have found an association between pancreatic cancer and the TERT or telomerase gene. Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether blood leukocyte telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR=1.26 95% CI=1.09-1.46; highest quartile compared to lowest, OR=1.57, 95% CI=1.01-2.43, p-trend=0.007). This effect remained for subjects diagnosed within the first five years of blood draw (continuous OR=1.46, 95% CI=1.19-1.79 highest quartile OR=2.92, 95%CI=1.47-5.77, p-trend=0.002), but not subjects diagnosed greater than five years from blood draw (continuous OR=1.03, 95%CI=0.85-1.22; highest quartile OR=1.04, 95%CI=0.60-1.79). This is the first study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk. Citation Format: Shannon M. Lynch, Jacqueline M. Major, Richard Cawthon, Stephanie J. Weinstein, Jarmo Virtamo, Qing Lan, Nathaniel Rothman, Demetrius Albanes, Rachael Z. Stolzenberg-Solomon. Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 13.

Pre-diagnostic circulating vitamin D and risk of melanoma in men.

PurposeVarious studies have examined the association between serum vitamin D levels and different cancers; however, this is the first prospective study of this association with melanoma risk. The aim of this study is to investigate the association between serum vitamin D [25(OH)D] levels and melanoma in a cohort of older, middle-aged Finnish male smokers.MethodsWe conducted a nested case-control study within the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study. From the ATBC cohort, 368 subjects were chosen for our study; 92 participants that developed melanoma and 276 matched control subjects. At study baseline, lifestyle questionnaires and blood samples were collected. Serum 25(OH)D was modeled as three sets of categorical variables: clinically-defined categories, season-specific quartiles and season-adjusted residual quartiles. Conditional logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs) to estimate the association between circulating vitamin D and melanoma risk.ResultsOverall no association of serum 25(OH)D and melanoma risk was observed. A decreased risk of developing melanoma was observed in the middle categories compared to the lowest category, albeit not significant.ConclusionResults indicate no association between serum 25(OH)D levels and melanoma. Additional studies, including possibly consortium efforts, are needed to investigate the association between serum 25(OH)D levels and risk of melanoma in larger, more diverse study populations.