Faculty Bibliography

Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; P(trend) = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; P(interaction) = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (</=222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E

Catechol-O-methyltransferase (COMT) is an important modulator in the catabolism of extraneural dopamine, which plays an important role in drug reward mechanisms. It is hypothesized that genetic variations in the COMT gene, which can result in a three to fourfold difference in COMT enzyme activity, may be associated with several reward-motivated behaviors. The aim of our study was to examine the relationship between COMT polymorphisms with smoking, obesity and alcohol. Three single nucleotide polymorphisms (SNPs) in COMT were genotyped in 2,371 participants selected randomly from the screening arm of the PLCO Cancer Screening Trial after stratifying by sex, age, and smoking status. Smoking, obesity, and alcohol consumption were assessed by questionnaire. SNP and haplotype associations were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from conditional logistic regression models, adjusted for race/ethnicity. The COMT Ex4-76C > G (Leu136Leu) polymorphism was statistically significantly associated with individuals who had >30% increases in BMI from ages 20 to 50 years, compared to those with 0-5% increase in BMI (0-5%) over the same age period: (CC is referent; OR(CG )= 1.42, OR(GG )= 1.46, P (trend )= 0.06). By sex, the increased risk was further pronounced among females (OR(CG )= 1.50, OR(GG )= 2.10, P (trend )= 0.03). Consistent with our analyses of single polymorphisms, individuals whose BMI increased >30% from ages 20 to 50 years were more likely than individuals with 0-5% increases in BMI to possess COMT haplotypes [COMT Ex3-104C > T-COMT Ex4-76 C > G-COMT Ex4-12 A > G] that included the variant allele for COMT Ex4-76 C > G: C-G-G (T-C-A is referent: OR(C-G-G )= 1.33, 95% CI 1.01-1.77) and C-G-A (OR(C-G-A )= 1.79, 95% CI 0.72-4.49). We observed no association between any of the COMT polymorphisms with smoking behavior or alcohol intake. The COMT Ex4-76C > G (Leu136Leu) polymorphism appears to play a role in large increases in BMI. The null association with smoking and alcohol and the pronounced association with increasing BMI among women further implicates COMT's role in estrogen metabolism as a potentially culpable pathway. Our results support a need for comprehensive evaluation of COMT variations and their functional relevance as COMT may be an important molecular target to evaluate for new treatments regarding obesity

To investigate a possible association between human herpesvirus 8 (HHV-8) and prostate cancer, we evaluated HHV-8 seroprevalence in 2 case-control studies. HHV-8 antibodies were detected by immunofluorescence with cells expressing lytic viral proteins and by enzyme immunoassays with recombinant viral structural protein (K8.1) and latent protein (latency-associated nuclear antigen-1; open reading frame 73), respectively. HHV-8 seroprevalence tended to be lower in patients with prostate cancer than in control subjects, but there was no significant difference in either study. These data imply that HHV-8 is not a major prevalent cause of prostate cancer

Epidemiological studies show that benzene exposure is associated with an increased incidence of leukemia and perhaps lymphoma. Chromosomal rearrangements are common in these hematopoietic diseases. Translocation t(14;18), the long-arm deletion of chromosome 6 [del(6q)], and trisomy 12 are frequently observed in lymphoma patients. Rearrangements of the MLL gene located on chromosome 11q23, such as t(4;11) and t(6;11), are common in therapy-related leukemias resulting from treatment with topoisomerase II inhibiting drugs. To examine numerical and structural changes in these chromosomes (2, 4, 6, 11, 12, 14, and 18), fluorescence in situ hybridization (FISH) was employed on metaphase spreads from workers exposed to benzene (n = 43) and matched controls (n = 44) from Shanghai, China. Aneuploidy (both monosomy and trisomy) of all seven chromosomes was increased by benzene exposure. Benzene also induced del(6q) in a dose-dependent manner (P(trend) = 0.0002). Interestingly, translocations between chromosomes 14 and 18, t(14;18), known to be associated with follicular non-Hodgkin lymphoma, were increased in the highly exposed workers (P < 0.001). On the other hand, translocations between chromosome 11 and other partner chromosomes that are found in therapy-induced leukemias were not increased. These data add weight to the notion that benzene can induce t(14;18) and del(6q) found in lymphoma, but do not support the idea that benzene induces t(4;11) or t(6;11). However, they do not rule out the possibility that other rearrangements of the MLL gene at chromosome 11q23 may be induced by benzene

Studies of pairwise interactions have shown that an alien plant can affect the pollination of a native plant, this effect being mediated by shared pollinators. Here we use a manipulative field experiment, to investigate the impact of the alien plant Impatiens glandulifera on an entire community of coflowering native plants. Visitation and pollen transport networks were constructed to compare replicated I. glandulifera invaded and I. glandulifera removal plots. Invaded plots had significantly higher visitor species richness, visitor abundance and flower visitation. However, the pollen transport networks were dominated by alien pollen grains in the invaded plots and consequently higher visitation may not translate in facilitation for pollination. The more generalized insects were more likely to visit the alien plant, and Hymenoptera and Hemiptera were more likely to visit the alien than Coleoptera. Our data indicate that generalized native pollinators can provide a pathway of integration for alien plants into native visitation systems

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci

BACKGROUND: The Gln allele of the Arg462Gln polymorphism in RNASEL results in a threefold decrease in enzymatic activity, a reported deficiency in apoptotic response, and has been associated with prostate cancer in some high-risk family studies. The relationship of this variant to sporadic prostate cancer remains uncertain. METHODS: We conducted a nested case-control study of 1,317 prostate cancer cases and 1,842 controls from the screening arm of the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. Conditional logistic regression was used to evaluate the association between the RNASEL Arg462Gln polymorphism and prostate cancer. RESULTS: No statistically significant association was observed between the Arg462Gln polymorphism and prostate cancer (compared to Arg/Arg, Gln/Arg: OR= 0.99 95% CI 0.84-1.16; Gln/Gln: OR= 0.95 95% CI 0.74-1.21), although slight non-significant differences in risk were observed among men with the Gln/Gln genotype by stage and grade. CONCLUSIONS: These results suggest that the RNASEL Gln/Gln genotype does not play an important role in the etiology of prostate cancer in the general population

BACKGROUND: At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. METHODS: We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case-control studies that included 10,244 head and neck cancer case subjects and 15,227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. All statistical tests were two-sided. RESULTS: Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% CI = 1.52 to 2.98), and there were clear dose-response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% CI = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% CI = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. CONCLUSIONS: Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology

BACKGROUND: Reports from several studies have suggested that carotenoids, and in particular lycopene, could be prostate cancer-preventive agents. This has stimulated extensive laboratory and clinical research, as well as much commercial and public enthusiasm. However, the epidemiologic evidence remains inconclusive. MATERIALS AND METHODS: We investigated the association between prediagnostic serum carotenoids (lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin) and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to examine methods of early detection and risk factors for cancer. The study included 692 incident prostate cancer cases, diagnosed 1 to 8 years after study entry, including 270 aggressive cases, with regional or distant stage (n = 90) or Gleason score >or=7 (n = 235), and 844 randomly selected, matched controls. As study participants were selected from those who were assigned to annual standardized screening for prostate cancer, results are unlikely to be biased by differential screening, a circumstance that is difficult to attain under non-trial conditions. RESULTS: No association was observed between serum lycopene and total prostate cancer [odds ratios (OR), 1.14; 95% confidence intervals (95% CI), 0.82-1.58 for highest versus lowest quintile; P for trend, 0.28] or aggressive prostate cancer (OR, 0.99; 95% CI, 0.62-1.57 for highest versus lowest quintile; P for trend, 0.433). beta-Carotene was associated with an increased risk of aggressive prostate cancer (OR, 1.67; 95% CI, 1.03-2.72 for highest versus lowest quintile; P for trend, 0.13); in particular, regional or distant stage disease (OR, 3.16; 95% CI, 1.37-7.31 for highest versus lowest quintile; P for trend, 0.02); other carotenoids were not associated with risk. CONCLUSION: In this large prospective study, high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer. Lycopene and other carotenoids were unrelated to prostate cancer. Consistent with other recent publications, these results suggest that lycopene or tomato-based regimens will not be effective for prostate cancer prevention