bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychosocial Factors Associated with an Increased Frequency of Prostate Cancer Screening in Men Ages 40 to 79 Years: The Olmsted County Study
Authors: Wallner Lauren P. , Sarma Aruna V. , Lieber Michael M. , St. Sauver Jennifer L. , Jacobson Debra J. , McGree Michaela E. , Gowan Monica E. , Jacobsen Steven J.
Published: December 2008

Prostate cancer is the second leading cause of cancer deaths among U.S. men. Early detection is associated with drastically improved 5-year survival rates. It is unclear, however, what psychosocial factors motivate or discourage men from taking advantage of both prostate-specific antigen (PSA) testing and digital rectal examination (DRE). The goal of the current study was to identify psychosocial factors that influence screening behavior for prostate cancer in a cohort of 2,447 men. In 1990, a randomly selected cohort of Caucasian men, ages 40 to 79 years, from Olmsted County, Minnesota, were enrolled in the study. These men completed a questionnaire containing queries on family history of prostate cancer, concern about getting prostate cancer, and marital status. Medical and laboratory records were reviewed to determine the number DREs (1989-1996) and PSA tests (1989-1998). Frequent screening was defined as the upper 25th percentile for number of DREs (>4) or PSAs (>3). Men who have a family history and men who worry or have concern about prostate cancer were more likely [odds ratio (OR), 1.5; 95% confidence interval (95% CI), 1.2-2.0 and OR, 1.9; 95% CI, 1.4-2.5] to seek screening compared with those without a family history or worry. The association between family history and frequent screening was similar in men who were married or living with someone (OR, 1.7; 95% CI, 1.2-2.2); however, it was reduced among men who live alone (OR, 0.6; 95% CI, 0.2-1.8). These data suggest that psychosocial factors such as family history, worry, or concern about prostate cancer and marital status may play an important role in men's decisions about prostate cancer screening. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3588–92)
Effects on Chinese Restaurant Workers of Exposure to Cooking Oil Fumes: A Cautionary Note on Urinary 8-Hydroxy-2′-Deoxyguanosine
Authors: Pan Chih-Hong , Chan Chang-Chuan , Wu Kuen-Yuh
Published: December 2008

This study evaluates oxidative DNA damage in workers who are exposed to cooking oil fumes (COFs) in Chinese restaurants. The study participants were 387 nonsmoking Chinese restaurant workers, 202 kitchen staff, and 185 service staff at 23 Chinese restaurants in Taiwan. Airborne particulate matter and particulate polycyclic aromatic hydrocarbon levels were monitored in kitchens and dining areas. Urinary 1-hydroxypyrene (1-OHP) was used as an internal dose of exposure to COFs, and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as an oxidative DNA damage marker. The relationship between workers' 8-OHdG and 1-OHP levels was estimated using linear mixed-effects models. Airborne particulate matter and polycyclic aromatic hydrocarbons levels in kitchens significantly exceeded those in dining areas. The kitchen staff's geometric mean levels of urinary 8-OHdG (7.9 μg/g creatinine) and 1-OHP (4.5 μg/g creatinine) were significantly higher than those of the service staff, which were 5.4 and 2.7 μg/g creatinine, respectively. Urinary 1-OHP level, work in kitchens, gender, and work hours per day were four significant predictors of urinary 8-OHdG levels after adjustments are made for covariates. Oxidative DNA damage was associated with exposure of Chinese restaurant workers to COFs. Female restaurant workers had a greater oxidative stress response to COFs than male restaurant workers, providing additional evidence of the link between lung cancer in Chinese women and exposure to COFs. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3351–7)
DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Yuen Hiu-Fung , Chan Yuen-Piu , Law Simon , Srivastava Gopesh , El-tanani Mohamed , Mak Tak-Wah , Chan Kwok-Wah
Published: December 2008

Recent studies have revealed an oncogenic role of DJ-1 through its ability to transform normal cells, prevent oxidative damage, and inhibit apoptosis. However, its role in esophageal squamous cell carcinoma (ESCC) is unknown. In this study, by immunohistochemistry, we analyzed the expression of DJ-1 in 81 ESCC tumors, 31 paired nonneoplastic esophageal epithelia, and 19 paired ESCC lymph node metastases. We found that cytoplasmic DJ-1 expression was significantly higher in ESCC and ESCC lymph node metastases than in nonneoplastic esophageal epithelium. ESCC specimens with high distant metastatic potential also had a significantly higher level of nuclear DJ-1 expression (P = 0.018). By Kaplan-Meier analysis, we found that a high level of nuclear DJ-1 was significantly associated with poorer patient survival in our cohort (P = 0.028). To investigate whether DJ-1 promotes ESCC progression through phosphatidylinositol 3-kinase pathway and modulation of apoptosis, we performed immunohistochemistry of pAkt and Daxx. We found that DJ-1 expression was significantly associated with pAkt, whereas nuclear DJ-1 expression was significantly correlated with nuclear expression of Daxx. These results suggest that phosphatidylinositol 3-kinase pathway and Daxx-regulated apoptosis might be important in DJ-1-mediated ESCC progression. By using multivariate Cox regression, we further showed that T4 stage (P = 0.003) and DJ-1 (P = 0.034) are independent predictors of patient survival. In conclusion, our results suggest that DJ-1 plays a very important role in transformation and progression of ESCC and may be used as a prognostic marker in ESCC. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3593–602)
Hyaluronan-Mediated Motility Receptor Gene Single Nucleotide Polymorphisms and Risk of Breast Cancer
Authors: Kalmyrzaev Bolot , Pharoah Paul D.P. , Easton Douglas F. , Ponder Bruce A.J. , Dunning Alison M. ,   for the SEARCH Team
Published: December 2008

A recent study used a network modeling strategy to generate a set of genes linked by potential functional associations. The hyaluronan-mediated motility receptor (HMMR) gene was identified as being as functionally associated with BRCA1 and thus a candidate breast cancer gene. SNPs rs10515860, rs299290, and rs7712023 were reported to be significantly associated with breast cancer in a joint analysis of two small case-control studies. We have examined the association of these single nucleotide polymorphisms, together with others tagging the HMMR gene, in a larger, European case-control study and find no association of any of them with risk of breast cancer: rs10515860 [odds ratio (OR; AA/GG), 0.85; 95% confidence interval (CI), 0.65-1.12; Ptrend = 0.9], rs299290 [OR (CC/TT), 1.00; 95% CI, 0.87-1.15; Ptrend = 0.7], rs3756648 (rs7712023) [OR (TT/CC), 0.93; 95% CI, 0.84-1.02; Ptrend = 0.1], rs299284 [OR (TT/CC), 1.01; 95% CI, 0.76-1.35; Ptrend = 0.5], and rs13183712 [OR (TT/GG), 1.04; 95% CI, 0.88-1.23; Ptrend = 0.6]. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3618–20)
Target Sequence Polymorphism of Human Manganese Superoxide Dismutase Gene and Its Association with Cancer Risk: A Review
Authors: Bag Arundhati , Bag Niladri
Published: December 2008

In normal state of a cell, endogenous antioxidant enzyme system maintains the level of reactive oxygen species generated by mitochondrial respiratory chain. Mitochondrial superoxide dismutase [SOD; manganese SOD (MnSOD) or SOD2] neutralizes highly reactive superoxide radical (O•-2), the first member in the plethora of mitochondrial reactive oxygen species. A polymorphism in the target sequence of MnSOD enzyme, Val16Ala, is known to disrupt proper targeting of the enzyme from cytosol to mitochondrial matrix where it acts on O•-2 to dismutate it to hydrogen peroxide (H2O2). A change in the level of O•-2 and of H2O2 in mitochondria modulates the molecular mechanisms of apoptosis, cellular adhesion, and cell proliferation and thus play key role in cancer development. Previous studies investigating the association between MnSOD Val16Ala polymorphism and cancer risk have revealed inconsistent results. We conducted a meta-analysis on these studies. Our meta-analysis on total of 7,366 cancer cases and 9,102 controls from 13 published case-control studies showed no overall association of this polymorphism either with breast cancer risk or for cancer risk as such (for Ala homozygous odds ratio, 0.98; 95% confidence interval, 0.90-1.07 and odds ratio, 1.02; 95% confidence interval, 0.91-1.14, respectively). Also, there was no major effect in either recessive or dominant model for the MnSOD Val16Ala. However, a proper evaluation of this polymorphism with cancer link demands experiments involving large sample size, cross-tabulation of gene-gene, gene-environment interactions, and linkage studies, as cell biological experiments clearly correlate critical levels of mitochondrial O•-2 and H2O2 to carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3298–305)
Nicotine Intake in Cigarette Smokers in England: Distribution and Demographic Correlates
Authors: Fidler Jennifer A. , Jarvis Martin J. , Mindell Jennifer , West Robert
Published: December 2008

Documenting smoke intake by objective biochemical markers is important for quantification of exposure to toxins. The aim of this report is to show the most definitive distribution of the nicotine metabolite, cotinine, yet available from English smokers in the period before implementation of the legislation banning smoking in indoor public areas. A total of 6,423 cigarette smokers, ages 16 years and above, taking part in the Health Survey for England between 1998 and 2003 provided a saliva cotinine value. Data on cigarette consumption, age, gender, social class, deprivation (as indicated by manual or nonmanual occupation, car ownership, and housing tenure), marital status, and region were collected. Cotinine concentrations showed no overall trend over the study period. The mean value was 289.15 ng/mL (SD 174.43); excluding those who had not smoked in the past 24 hours, the mean value was 302.08 ng/mL (SD 168.78). A higher cotinine concentration was associated with being middle-aged (peaking at 40 years), being male, being single, greater economic deprivation, and not living in London. After adjusting for cigarette consumption, higher values were associated with middle age, being male, and greater deprivation. This study provides the most complete picture yet of the smoke intake of cigarette smokers in England. The fact that cotinine peaks at around the age of 40 years raises the possibility that nicotine intake continues to increase decades after a person starts to smoke. Greater nicotine intake in more deprived smokers could explain why they find it harder to stop smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3331–6)
Exposure to a Tobacco-Specific Lung Carcinogen in Adolescent versus Adult Smokers
Authors: Hertsgaard Louise A. , Hanson Karen , Hecht Stephen S. , Lindgren Bruce R. , Luo Xianghua , Carmella Steven G. , Riley William T. , Zylla Emily B. , Murphy Sharon E. , Hatsukami Dorothy K.
Published: December 2008

Background: Previous studies with adult smokers have shown an association between number of cigarettes smoked per day (CPD) and levels of biomarkers of exposure to the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). This study compared carcinogen and nicotine exposure in adolescent and adult smokers across categories of CPD.

Method: Baseline smoking history and biomarker data were merged from six studies to make two samples: one of adolescent smokers and one of adult smokers. Metabolites of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and its glucuronides (NNAL-Gluc) and total cotinine were quantified in urine.

Results: CPD was stratified into categories of 5 to 10, 11 to 15, and 16 to 20 CPD. Adolescents tended to have lower mean levels of NNAL plus NNAL-Glucs (total NNAL) compared with adults, although differences were not significant overall. Adolescent mean levels of NNAL/CPD were significantly lower than adult levels only in the 11 to 15 CPD category (P = 0.045). However, a significant positive relationship was observed for total NNAL/CPD by age. No significant differences between adolescents and adults were found in mean levels of total cotinine or cotinine/CPD. A subsample of urines from adolescents and adults were analyzed for NNAL-Glucs and NNAL. Adolescents and adults did not significantly differ in the ratio of NNAL-Glucs to NNAL.

Conclusions: Adolescent uptake of NNK and nicotine tends to be lower although not statistically different from adults. The lack of significant differences may be due to the wide variation in exposure in adolescents. Some adolescent smokers are exposed to lung carcinogens at levels similar to those of adults. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3337–43)
Reproducibility and Correlations of Multiplex Cytokine Levels in Asymptomatic Persons
Authors: Wong Hui-Lee , Pfeiffer Ruth M. , Fears Thomas R. , Vermeulen Roel , Ji Shaoquan , Rabkin Charles S.
Published: December 2008

Rationale: Cytokines are humoral regulatory molecules that act together in immunologic pathways underlying pathogenesis. Grossly elevated blood levels characterize certain diseases; variations within physiologic ranges could also have significance. We therefore evaluated the performance characteristics of a multiplex cytokine immunoassay.

Methods: We used a fluorescent bead-based (Luminex) immunoassay kit to simultaneously measure interleukin (IL) 1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12p70, IL13, IFNγ, granulocyte colony-stimulating factor, and tumor necrosis factor-α. We tested identical aliquots of serum from 38 asymptomatic individuals on three different days and matched sets of serum, heparinized plasma, and acid citrate dextrose plasma from an additional 38 healthy donors expected to have low cytokine concentrations. We applied multiple imputation to calculate unbiased reproducibility estimates for measurements below the limits of detection. Correlations among the cytokines were assessed by Spearman rank order coefficients and principal components analyses.

Results: Of the 13 cytokines, 3 were undetectable (IL1β, IL2, IL5) in more than half of the serum samples. Coefficients of variation for replicate serum measurements ranged from 18% to 44%, with intraclass correlation coefficients ranging from 55% to 98%. Only IL4, IL6, and IL8 had statistically significant correlations (Spearman ρ, 0.42-0.94) between serum and acid citrate dextrose or heparin plasma levels.

Conclusions: Interindividual differences outweigh substantial laboratory variation for these assays, yielding high intraclass correlation coefficients despite unimpressive coefficients of variation. Plasma measurements generally are not reflective of serum levels and hence are not interchangeable. With their small volume, low cost per test, and multiplex capacity, Luminex-based cytokine assays have potential utility for epidemiologic studies. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3450–6)
Alcohol Consumption and Mutations or Promoter Hypermethylation of thevon Hippel–LindauGene in Renal Cell Carcinoma
Authors: Schouten Leo J. , van Dijk Boukje A.C. , Oosterwijk Egbert , van Engeland Manon , Hulsbergen–van de Kaa Christina A. , Kiemeney Lambertus A.L.M. , Goldbohm Royle Alexandra , Kester Arnold , de Vogel Stefan , Schalken Jack A. , van den Brandt Piet A.
Published: December 2008

Alcohol consumption has been associated with a decreased risk for renal cell cancer in several studies. We investigated whether alcohol is associated with (epi)genetic changes of the von Hippel–Lindau (VHL) gene in renal cell cancer. The Netherlands Cohort Study (NLCS) on Diet and Cancer started in 1986 (n = 120,852) and uses the case-cohort method. After 11.3 years of follow-up, 314 renal cell cancer cases and 4,511 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumor tissue from 235 cases. VHL mutations were analyzed by sequencing, whereas VHL promoter methylation was analyzed using methylation-specific PCR. In multivariate analysis, hazard ratios of renal cell cancer for cohort members who consumed up to 5, 15, 30, and ≥30 g of alcohol per day were 0.72, 0.64, 0.81, and 0.69, respectively, compared with nondrinkers [95% confidence interval (95% CI) for the ≥30 category, 0.44-1.07; P for trend, 0.17]. Alcohol intake from beer, wine, and liquor was associated with decreased risks for renal cell cancer, although not statistically significant. Hazard ratios were not different for clear-cell renal cell cancer with and without VHL mutations, except for alcohol from beer, which was associated with an increased risk for clear-cell renal cell cancer without VHL mutations (hazard ratio for ≥5 g of alcohol from beer compared with nondrinkers, 2.74; 95% CI, 1.35-5.57). Alcohol was associated with a decreased risk for clear-cell renal cell cancer without VHL gene promoter methylation (hazard ratio for >15 g compared with nondrinkers, 0.58; 95% CI, 0.34-0.99). In this study, a not statistically significant inverse association was observed between alcohol and renal cell cancer. There was no statistical significant heterogeneity by VHL mutation or methylation status. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3543–50)
Anthocyanin/Polyphenolic–Rich Fruit Juice Reduces Oxidative Cell Damage in an Intervention Study with Patients on Hemodialysis
Authors: Spormann Thomas M. , Albert Franz W. , Rath Thomas , Dietrich Helmut , Will Frank , Stockis Jean-Pierre , Eisenbrand Gerhard , Janzowski Christine
Published: December 2008

Hemodialysis patients face an elevated risk of cancer, arteriosclerosis, and other diseases, ascribed in part to increased oxidative stress. Red fruit juice with high anthocyanin/polyphenol content had been shown to reduce oxidative damage in healthy probands. To test its preventive potential in hemodialysis patients, 21 subjects in a pilot intervention study consumed 200 mL/day of red fruit juice (3-week run-in; 4-week juice uptake; 3-week wash-out). Weekly blood sampling was done to monitor DNA damage (comet assay ± formamidopyrimidine-DNA glycosylase enzyme), glutathione, malondialdehyde, protein carbonyls, trolox equivalent antioxidant capacity, triglycerides, and DNA binding capacity of the transcription factor nuclear factor-κB. Results show a significant decrease of DNA oxidation damage (P < 0.0001), protein and lipid peroxidation (P < 0.0001 and P < 0.001, respectively), and nuclear factor-κB binding activity (P < 0.01), and an increase of glutathione level and status (both P < 0.0001) during juice uptake. We attribute this reduction in oxidative (cell) damage in hemodialysis patients to the especially high anthocyanin/polyphenol content of the juice. This provides promising perspectives into the prevention of chronic diseases such as cancer and cardiovascular disease in population subgroups exposed to enhanced oxidative stress like hemodialysis patients. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3372–80)
Mammographic Breast Density—Evidence for Genetic Correlations with Established Breast Cancer Risk Factors
Authors: Douglas Julie A. , Roy-Gagnon Marie-Hélène , Zhou Chuan , Mitchell Braxton D. , Shuldiner Alan R. , Chan Heang-Ping , Helvie Mark A.
Published: December 2008

Previous twin and family studies indicate that the familial aggregation of breast density is due (in part) to genetic factors. Whether these genetic influences are shared with other breast cancer risk factors, however, is not known. Using standard film-screen mammography, we screened 550 women, including 611 pairs of sisters, from the Old Order Amish population of Lancaster County, Pennsylvania. We digitized mammograms and quantified the dense and nondense areas of the breast using a computer-assisted method. Information about other breast cancer risk factors was collected via questionnaires and a physical exam. Using pedigree-based variance component methods, we estimated the genetic contributions to several breast cancer risk factors, including breast density, and evaluated the evidence for shared genetic influences between them. After adjusting for covariates, genetic effects accounted for >33% of the total variance of each risk factor (P < 0.001), including breast density, and the dense and nondense areas of the breast were significantly genetically correlated with parity [genetic correlation (ρG) = -0.47; P = 0.013] and age at menarche (ρG = -0.38; P = 0.008), respectively. The nondense area of the breast and, in turn, breast density, expressed as a ratio of dense area to total area, were also genetically correlated with most measures of adiposity but in opposite directions (ρG ≥ 0.75; P < 10−7 for nondense area). We conclude that the genetic components that influence breast density are not independent of the genetic components that influence other breast cancer risk factors. This shared genetic architecture should be considered in future genetic studies of breast density. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3509–16)
Whole-Genome Amplification Enables Accurate Genotyping for Microarray-Based High-Density Single Nucleotide Polymorphism Array
Authors: Jasmine Farzana , Ahsan Habibul , Andrulis Irene L. , John Esther M. , Chang-Claude Jenny , Kibriya Muhammad G.
Published: December 2008

In large-scale genome-wide association studies based on high-density single nucleotide polymorphism (SNP) genotyping array, the quantity and quality of available genomic DNA (gDNA) is a practical problem. We examined the feasibility of using the Multiple Displacement Amplification (MDA) method of whole-genome amplification (WGA) for such a platform. The Affymetrix Early Access Mendel Nsp 250K GeneChip was used for genotyping 224,940 SNPs per sample for 28 DNA samples. We compared the call concordance using 14 gDNA samples and their corresponding 14 WGA samples. The overall mean genotype call rates in gDNA and the corresponding WGA samples were comparable at 97.07% [95% confidence interval (CI), 96.17-97.97] versus 97.77% (95% CI, 97.26-98.28; P = 0.154), respectively. Reproducibility of the platform, calculated as concordance in duplicate samples, was 99.45%. Overall genotypes for 97.74% (95% CI, 97.03-98.44) of SNPs were concordant between gDNA and WGA samples. When the analysis was restricted to well-performing SNPs (successful genotyping in gDNA and WGA in >90% of samples), 99.11% (95% CI, 98.80-99.42) of the SNPs, on average, were concordant, and overall a SNP showed a discordant call in 0.92% (95% CI, 0.90-0.94) of paired samples. In a pair of gDNA and WGA DNA, similar concordance was reproducible on Illumina's Infinium 610 Quad platform as well. Although copy number analysis revealed a total of seven small telomeric regions in six chromosomes with loss of copy number, the estimated genome representation was 99.29%. In conclusion, our study confirms that high-density oligonucleotide array-based genotyping can yield reproducible data and MDA-WGA DNA products can be effectively used for genome-wide SNP genotyping analysis. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3499–508)
Effect of Physical Activity on Breast Cancer Risk: Findings of the Japan Collaborative Cohort Study
Authors: Suzuki Sadao , Kojima Masayo , Tokudome Shinkan , Mori Mitsuru , Sakauchi Fumio , Fujino Yoshihisa , Wakai Kenji , Lin Yingsong , Kikuchi Shogo , Tamakoshi Koji , Yatsuya Hiroshi , Tamakoshi Akiko ,   for the Japan Collaborative Cohort Study Group
Published: December 2008

Purpose: This study aimed to examine prospectively the association between physical activity and breast cancer risk in a non-Western population.

Methods: We analyzed data from the Japan Collaborative Cohort Study, which included 30,157 women, ages 40 to 69 years at baseline (1988-1990), who reported no previous history of breast cancer, and provided information on their walking and exercise habits. The subjects were followed prospectively from enrollment until 2001 (median follow-up period, 12.4 years). Breast cancer incidence during this period was confirmed using records held at population-based cancer registries. The Cox proportional hazards model was used to estimate the hazard ratio (HR) for the association of breast cancer incidence with physical activity.

Results: During the 340,055 person-years of follow-up, we identified 207 incident cases of breast cancer. The most physically active group (who walked for ≥1 hour per day and exercised for ≥1 hour per week) had a lower risk of breast cancer (HR, 0.45; 95% confidence interval, 0.25-0.78) compared with the least active group after adjusting for potential confounding factors. The inverse association of exercise on breast cancer was stronger among those who walked for ≥1 hour per day than those who walked for <1 hour per day (P = 0.042). These results were not significantly modified by menopausal status or body mass index (BMI).

Conclusions: Our analysis provided evidence that physical activity decreased the risk of breast cancer. Walking for 1 hour per day and undertaking additional weekly exercise both seemed to be protective against breast cancer, regardless of menopausal status or BMI. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3396–401)
Polymorphism in theIL18Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women
Authors: Palmieri Rachel T. , Wilson Melanie A. , Iversen Edwin S. , Clyde Merlise A. , Calingaert Brian , Moorman Patricia G. , Poole Charles , Anderson A. Rebecca , Anderson Stephanie , Anton-Culver Hoda , Beesley Jonathan , Hogdall Estrid , Brewster Wendy , Carney Michael E. , Chen Xiaoqing , Chenevix-Trench Georgia , Chang-Claude Jenny , Cunningham Julie M. , DiCioccio Richard A. , Doherty Jennifer A. , Easton Douglas F. , Edlund Christopher K. , Gayther Simon A. , Gentry-Maharaj Aleksandra , Goode Ellen L. , Goodman Marc T. , Kjaer Susanne Kruger , Hogdall Claus K. , Hopkins Michael P. , Jenison Eric L. , Blaakaer Jan , Lurie Galina , McGuire Valerie , Menon Usha , Moysich Kirsten B. , Ness Roberta B. , Pearce Celeste Leigh , Pharoah Paul D.P. , Pike Malcolm C. , Ramus Susan J. , Rossing Mary Anne , Song Honglin , Terada Keith Y. , VanDenBerg David , Vierkant Robert A. , Wang-Gohrke Shan , Webb Penelope M. , Whittemore Alice S. , Wu Anna H. , Ziogas Argyrios , Berchuck Andrew , Schildkraut Joellen M. ,   On behalf of the Ovarian Cancer Association Consortium; Australian Cancer Study (Ovarian Cancer Group); Australian Ovarian Cancer Study Group
Published: December 2008

Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567–72)
Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk
Authors: Pooley Karen A. , Baynes Caroline , Driver Kristy E. , Tyrer Jonathan , Azzato Elizabeth M. , Pharoah Paul D.P. , Easton Douglas F. , Ponder Bruce A.J. , Dunning Alison M.
Published: December 2008

The proteins involved in homologous recombination are instrumental in the error-free repair of dsDNA breakages, and common germ-line variations in these genes are, therefore, potential candidates for involvement in breast cancer development and progression. We carried out a search for common, low-penetrance susceptibility alleles by tagging the common variation in 13 genes in this pathway in a two-stage case-control study. We genotyped 100 single-nucleotide polymorphisms (SNP), tagging the 655 common SNPs in these genes, in up to 4,470 cases and 4,560 controls from the SEARCH study. None of these tagging SNPs was associated with breast cancer risk, with the exception of XRCC2 rs3218536, R188H, which showed some evidence of a protective association for the rare allele [per allele odds ratio, 0.89; 95% confidence intervals (95% CI), 0.80-0.99; P trend = 0.03]. Further analyses showed that this effect was confined to a risk of progesterone receptor positive tumors (per rare allele odds ratio, 0.78; 95% CI, 0.66-0.91; P trend = 0.002). Several other SNPs also showed receptor status-specific susceptibility and evidence of roles in long-term survival, with the rare allele of BRIP1 rs2191249 showing evidence of association with a poorer prognosis (hazard ratio per minor allele, 1.20; 95% CI, 1.07-1.36; P trend = 0.002). In summary, there was little evidence of breast cancer susceptibility with any of the SNPs studied, but larger studies would be needed to confirm subgroup effects. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3482–9)
Melatonin as a Biomarker of Circadian Dysregulation
Authors: Mirick Dana K. , Davis Scott
Published: December 2008

It would be most useful to identify a biomarker of circadian dysregulation that could be used in epidemiologic studies of the effects of circadian disruption in humans. An indicator of circulating melatonin level has been shown to be a good biomarker of circadian dysregulation and has been associated with nightshift work and exposure to light-at-night in both laboratory-based and field studies. Among other circadian markers (such as core body temperature), it remains comparatively robust in the presence of various external influences. It can be reliably measured directly and indirectly through its metabolites in urine, blood, and saliva. Urinary melatonin has been shown to be stable over time, making it useful in epidemiologic studies in which laboratory processing is not immediately available, as well as studies of cancer with long latency periods. Several studies have shown melatonin to be useful in measuring diurnal type, which is of increasing interest as it becomes more apparent that successful adaptation to shift work may be dependent on diurnal preference. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3306–13)
Influence of Evolution in Tumor Biobanking on the Interpretation of Translational Research
Authors: Barnes Rebecca O. , Parisien Michelle , Murphy Leigh C. , Watson Peter H.
Published: December 2008

Purpose: Translational cancer research increasingly relies on human tissue biospecimens and this has coincided with a shift in tissue biobanking approach. Newer biobanks (post year 2000) deploy standard operating procedures to reduce variability around biospecimen collection. Because current translational research is based on pre-2000 and post-2000 era biospecimens, we consider whether the collection era may influence gene expression data.

Design: We compared the range of breast tumor collection times from pre-2000 and post-2000 era biobanks and compared estrogen receptor (ER) protein expression with collection time. We then collected 10 breast tumor biospecimens under a standardized protocol and examined whether the expression of c-myc and ER was influenced by storage on ice ≤24 hours.

Results: The range of collection times achieved at a pre-2000 versus post-2000 era biobank differed. Thirty-two percent of biospecimens were cryopreserved within 30 minutes at the pre-2000 era biobank versus 76% at the post-2000 era biobank. Collection time and ER protein level was inversely correlated (r = −0.19, P = 0.025; n = 137). We observed a wide range in initial c-myc and ER mRNA levels (50- versus 130-fold). Although mRNA levels of both genes declined with increasing collection time, the rate of change differed because c-myc was significantly reduced after 24 hours (mean reduction to 79% of initial) versus ER (94% of initial).

Conclusion: The overall shift in biobanking around the year 2000 is reflected in the ranges of collection times associated with pre-2000 and post-2000 era biobanks. Because collection time can differentially alter gene expression, the biospecimen collection era should be considered in gene expression studies. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3344–50)
Risk Factors for Classical Kaposi Sarcoma in a Population-based Case-control Study in Sicily
Authors: Anderson Lesley A. , Lauria Carmela , Romano Nino , Brown Elizabeth E. , Whitby Denise , Graubard Barry I. , Li Yan , Messina Angelo , Gafà Lorenzo , Vitale Francesco , Goedert James J.
Published: December 2008

Background: Classical Kaposi sarcoma is a rare complication of Kaposi sarcoma-associated herpes virus (KSHV) infection. We conducted a population-based, frequency-matched case-control study in Sicily to further investigate the reported inverse relationship between smoking and classical Kaposi sarcoma and to identify other factors associated with altered risk.

Methods: All incident, histologically confirmed classical Kaposi sarcoma cases in Sicily were eligible. A two-stage cluster sample design was applied to select population controls. KSHV seropositivity was determined using four antibody assays (K8.1 and orf73 enzyme immunoassays and two immunofluorenscence assays). Using SAS-callable SUDAAN, we compared the characteristics of classical Kaposi sarcoma cases and KSHV-seropositive controls. Odds ratios (OR) and 95% confidence intervals (CI) are presented.

Results: In total, 142 classical Kaposi sarcoma cases and 123 KSHV-seropositive controls were recruited. Current cigarette smoking was associated with reduced risk of classical Kaposi sarcoma amongst males (OR, 0.20; 95% CI, 0.06-0.67). Edema was associated with classical Kaposi sarcoma, but only when it presented on the lower extremities (OR, 3.65; 95% CI, 1.62-8.23). Irrespective of presentation site, diabetes and oral corticosteroid medications were associated with increased risk (OR, 4.73; 95% CI, 2.02-11.1 and OR, 2.34; 95% CI, 1.23-4.45, respectively). Never smoking, diabetes, and oral corticosteroid medication use were all independently associated with classical Kaposi sarcoma risk.

Discussion: We confirmed previous reports that cigarette smoking was associated with a reduced risk of classical Kaposi sarcoma, and we found that risk was lowest among current smokers. We also found that classical Kaposi sarcoma risk was strongly and independently associated with oral corticosteroid use and diabetes. Corroboration of these observations and investigation of possible underlying mechanisms are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3435–43)
Folate Intake and Risk of Breast Cancer by Estrogen and Progesterone Receptor Status in a Swedish Cohort
Authors: Larsson Susanna C. , Bergkvist Leif , Wolk Alicja
Published: December 2008

Background: Folate is a B vitamin involved in one-carbon metabolism and has been postulated to influence the risk of breast cancer. However, epidemiologic studies of folate intake in relation to breast cancer risk are inconclusive. We examined the association between dietary folate intake and the risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR) status of the breast tumor in the Swedish Mammography Cohort.

Methods: Our study population consisted of 61,433 women who completed a food frequency questionnaire at baseline (1987-1990) and again in 1997. Cox proportional hazards models were used to estimate rate ratios (RR) with 95% confidence intervals (95% CI).

Results: During an average of 17.4 years of follow-up, 2,952 incident cases of invasive breast cancer were ascertained. We observed no association between dietary folate intake and risk of total breast cancer or ER+/PR+ or ER-/PR- tumors. The multivariate RR of total breast cancer comparing extreme quintiles of folate intake was 1.01 (95% CI, 0.90-1.13; Ptrend = 0.84). However, folate intake was inversely associated with risk of ER+/PR- breast cancer (n = 417 cases; RR for highest versus lowest quintile, 0.79; 95% CI, 0.59-1.07; Ptrend = 0.01). Results did not vary by alcohol intake or menopausal status.

Conclusions: These findings do not support an overall association between folate intake and risk of breast cancer but suggest that folate intake may be inversely associated with ER+/PR− tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3444–9)
Perils in the Use of Linkage Disequilibrium for Fine Gene Mapping: Simple Insights from Population Genetics
Authors: Gorroochurn Prakash
Published: December 2008

It is generally believed that genome-wide association (GWA) studies stand a good chance for finding susceptibility genes for common complex diseases. Although the results thus far have been somewhat promising, there are still many inherent difficulties and many initial associations do not get replicated. The common strategy in GWA studies has been that of selecting the most statistically significant single nucleotide polymorphisms with the hope that these will be very physically close to causal variants because of strong linkage disequilibrium (LD). Using simple ideas from population genetics, this commentary explains why this strategy can be misleading. It argues that there is an intrinsic problem in the way LD is currently used for fine-mapping. This is because most of the metrics that are currently used to measure LD are inadequate, as they do not take into account evolutionary variables that shape the LD structure of the human genome. Recent research on another metric, based on Malécot's model for isolation by distance, holds considerable promise for GWA studies and merits more serious consideration by geneticists. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3292–7)
Correlation between the Urine Profile of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Metabolites and N7-Methylguanine in Urothelial Carcinoma Patients
Authors: Lee Hui-Ling , Hsueh Yu-Mei , Chung Chi-Jung , Pu Yeong-Shiau , Chang Louis W. , Hsieh Dennis Paul Hsientang , Liou Saou-Hsing , Lin Pinpin
Published: December 2008

A major carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in cigarette smoke and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is used as an exposure biomarker for environmental tobacco smoke (ETS). This metabolite (NNAL) can be either detoxified into glucuronidated NNAL (NNAL-Gluc) or activated into an unstable reactive metabolite that methylates DNA along with formation of 4-hydroxy-4-(3-pyridyl)-butyric acid [hydroxy acid (HA)]. Therefore, the carcinogenic risk associated with ETS exposure is greatly modulated by individual variations in metabolic activation and detoxification capabilities. In this study, we defined the urinary HA/total NNAL [HA/total NNAL] ratio as the activation index and NNAL-Gluc/free NNAL [(total NNAL-free NNAL)/free NNAL] ratio as the detoxification index of NNK. The major methylated DNA adduct N7-methylguanine (N7-MeG), considered as the carcinogenic biomarker for cigarette smoking, was excreted in urine. The objective of this study was to investigate the effects of these metabolic indexes of NNK on N7-MeG urinary excretion in a population of urothelial carcinoma patients. Urinary levels of total NNAL (free NNAL plus NNAL-Gluc), free NNAL, HA, and N7-MeG were positively correlated with smoking. Furthermore, activation index and detoxification index correlated positively and negatively with N7-MeG levels, respectively. Our results suggest that these metabolic indices may represent the phenotype of individual metabolism capability and modulate the carcinogenic risk of ETS exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3390–5)
No Association of Single Nucleotide Polymorphisms in One-Carbon Metabolism Genes with Prostate Cancer Risk
Authors: Stevens Victoria L. , Rodriguez Carmen , Sun Juzhong , Talbot Jeffrey T. , Thun Michael J. , Calle Eugenia E.
Published: December 2008

One-carbon metabolism mediates the interconversion of folates for the synthesis of precursors used in DNA synthesis, repair, and methylation. Inadequate folate nutrition or compromised metabolism can disrupt these processes and facilitate carcinogenesis. In this study, we investigated associations of 39 candidate single nucleotide polymorphisms (SNP) in 9 one-carbon metabolism genes with risk of prostate cancer using 1,144 cases and 1,144 controls from the Cancer Prevention Study-II Nutrition Cohort. None of these SNPs were significantly associated with prostate cancer risk, either overall or in cases with advanced prostate cancer. Thus, our findings do not support the hypothesis that common genetic variation in one-carbon metabolism genes influences prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3612–4)
Gene Signaling Pathways Mediating the Opposite Effects of Prepubertal Low-Fat and High-Fat n-3 Polyunsaturated Fatty Acid Diets on Mammary Cancer Risk
Authors: Olivo-Marston Susan E. , Zhu Yuelin , Lee Richard Y. , Cabanes Anna , Khan Galam , Zwart Alan , Wang Yue , Clarke Robert , Hilakivi-Clarke Leena
Published: December 2008

In rats, prepubertal exposure to low-fat diet containing n-3 polyunsaturated fatty acids (PUFA) reduces mammary cell proliferation, increases apoptosis, and lowers risk of mammary tumors in adulthood, whereas prepubertal high-fat n-3 PUFA exposure has opposite effects. To identify signaling pathways mediating these effects, we performed gene microarray analyses and determined protein levels of genes related to mammary epithelial cell proliferation. Nursing female rats and rat pups were fed low-fat (16% energy from fat) or high-fat (39% energy from fat) n-3 or n-6 PUFA diets between postnatal days 5 and 24. cDNA gene expression microarrays were used to identify global changes in the mammary glands of 50-day-old rats. Differences in gene expression were confirmed by real-time quantitative PCR, and immunohistochemistry was used to assess changes in the peroxisome proliferator–activated receptor γ and cyclin D1 levels. DNA damage was determined by 8-hydroxy-2′-deoxyguanosine assay. Expressions of the antioxidant genes thioredoxin, heme oxygenase, NADP-dependent isocitrate dehydrogenase, and metallothionein III, as well as peroxisome proliferator–activated receptor γ protein, were increased in the mammary glands of 50-day-old rats prepubertally fed the low-fat n-3 PUFA diet. Prepubertal exposure to the high-fat n-3 PUFA diet increased DNA damage and cyclin D1 protein and reduced expression of BRCA1 and cardiotrophin-1. Reduction in mammary tumorigenesis among rats prepubertally fed a low-fat n-3 PUFA diet was associated with an up-regulation of antioxidant genes, whereas the increase in mammary tumorigenesis in the high-fat n-3 PUFA fed rats was linked to up-regulation of genes that induce cell proliferation and down-regulation of genes that repair DNA damage and induce apoptosis.
Grape Seed Extract Inhibits Angiogenesis via Suppression of the Vascular Endothelial Growth Factor Receptor Signaling Pathway
Authors: Wen Wei , Lu Jianming , Zhang Keqiang , Chen Shiuan
Published: December 2008

Blockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase–mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.
Longitudinal Assessment of Air Conduction Audiograms in a Phase III Clinical Trial of Difluoromethylornithine and Sulindac for Prevention of Sporadic Colorectal Adenomas
Authors: McLaren Christine E. , Fujikawa-Brooks Sharon , Chen Wen-Pin , Gillen Daniel L. , Pelot Daniel , Gerner Eugene W. , Meyskens Frank L.
Published: December 2008

A phase III clinical trial assessed the recurrence of adenomatous polyps after treatment for 36 months with difluoromethylornithine (DFMO) plus sulindac or matched placebos. Temporary hearing loss is a known toxicity of treatment with DFMO, thus a comprehensive approach was developed to analyze serial air conduction audiograms. The generalized estimating equation method estimated the mean difference between treatment arms with regard to change in air conduction pure tone thresholds while accounting for within-subject correlation due to repeated measurements at frequencies. Based on 290 subjects, there was an average difference of 0.50 dB between subjects treated with DFMO plus sulindac compared with those treated with placebo (95% confidence interval, −0.64 to 1.63 dB; P = 0.39), adjusted for baseline values, age, and frequencies. In the normal speech range of 500 to 3,000 Hz, an estimated difference of 0.99 dB (−0.17 to 2.14 dB; P = 0.09) was detected. Dose intensity did not add information to models. There were 14 of 151 (9.3%) in the DFMO plus sulindac group and 4 of 139 (2.9%) in the placebo group who experienced at least 15 dB hearing reduction from baseline in 2 or more consecutive frequencies across the entire range tested (P = 0.02). Follow-up air conduction done at least 6 months after end of treatment showed an adjusted mean difference in hearing thresholds of 1.08 dB (−0.81 to 2.96 dB; P = 0.26) between treatment arms. There was no significant difference in the proportion of subjects in the DFMO plus sulindac group who experienced clinically significant hearing loss compared with the placebo group. The estimated attributable risk of ototoxicity from exposure to the drug is 8.4% (95% confidence interval, −2.0% to 18.8%; P = 0.12). There is a <2 dB difference in mean threshold for patients treated with DFMO plus sulindac compared with those treated with placebo.