bluuebunny/crossref_metadata_2025 huggingface dataset:
The Molecular Signature of Normal Squamous Esophageal Epithelium Identifies the Presence of a Field Effect and Can Discriminate between Patients with Barrett's Esophagus and Patients with Barrett's-Associated Adenocarcinoma
Authors: Brabender Jan , Marjoram Paul , Lord Reginald V.N. , Metzger Ralf , Salonga Dennis , Vallböhmer Daniel , Schäfer Hartmut , Danenberg Kathleen D. , Danenberg Peter V. , Selaru Florin M. , Baldus Stefan E. , Hölscher Arnulf H. , Meltzer Stephen J. , Schneider Paul M.
Published: September 2005

Background and Aim: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the esophagus disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous esophagus epihelium of patients with Barrett's esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's disease.

Methods: Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis.

Results: A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARα, RARγ, RXRα, RXRβ, SPARC, TSPAN, and VEGF. Based on the expression signature of the normal appearing squamous esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%.

Conclusion: This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's esophagus disease. Based on the gene expression signature of the normal esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's esophagus disease.
Serum Concentrations of Estrogens, Sex Hormone Binding Globulin, and Androgens and Risk of Breast Hyperplasia in Postmenopausal Women
Authors: Schairer Catherine , Hill Deirdre , Sturgeon Susan R. , Fears Thomas , Mies Carolyn , Ziegler Regina G. , Hoover Robert N. , Sherman Mark E.
Published: September 2005

Objective: We sought to determine whether serum concentrations of estrogens, androgens, and sex hormone binding globulin in postmenopausal women were related to the presence of mammary hyperplasia, an established breast cancer risk factor.

Methods: Study participants provided serum before breast biopsy or mastectomy in three hospitals in Grand Rapids, Michigan, between 1977 and 1987. A total of 179 subjects with breast hyperplasia were compared with 152 subjects with nonproliferative breast changes that are not associated with increased breast cancer risk.

Results: The odds ratios (OR) associated with the three upper quartiles of estradiol in comparison with the lowest quartile were 2.2 [95% confidence interval (95% CI) 1.1-4.6], 2.5 (95% CI, 1.1-5.3), and 4.1 (95% CI, 2.0-8.5; Ptrend = 0.007). The corresponding ORs for bioavailable estradiol, estrone, and estrone sulfate were of generally similar magnitude (Ptrend = 0.003 for bioavailable estradiol, 0.0004 for estrone, and 0.0009 for estrone sulfate). Relative to women concurrently in the lowest tertile for serum estradiol, estrone, and estrone sulfate, women concurrently in the highest tertile for all three hormones had an OR of 5.8 (95% CI, 2.2-15.2). Serum concentrations of sex hormone binding globulin, testosterone, dehydroepiandrosterone, androstenedione, and androstenediol were not associated with risk of hyperplasia.

Conclusions: Serum concentrations of estrogens, but not of androgens or sex hormone binding globulin, were strongly and significantly associated with risk of breast hyperplasia in postmenopausal women, suggesting that estrogens are important early in the pathologic process towards breast cancer.
Statins and Cancer Development
Authors: Duncan Robin E. , El-Sohemy Ahmed , Archer Michael C.
Published: September 2005

There is epidemiologic evidence that the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin increases the incidence of some extrahepatic cancers, although this finding has been attributed to chance. We hypothesize that pravastatin is able to promote the development of cancer by causing an induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic tissues. We have shown that mevalonate, the product of HMG-CoA reductase, promotes the growth of breast cancer cells. Because there is no uptake of pravastatin by most extrahepatic cells, this statin will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol caused by its inhibition of hepatic HMG-CoA reductase.
Etiology of Gastric Cancer: What Is New?
Authors: Correa Pelayo , Schneider Barbara G.
Published: September 2005

Recent advances in understanding of risk factors for gastric cancer have focused attention on genetic polymorphisms in both the human host and in Helicobacter pylori. Variation in genes for cytokines such as interleukin-1β and its receptor antagonist may allow identification of those individuals predisposed to mount an immune response that puts them at elevated risk for gastric cancer. Likewise, analysis of how genetic variation in the genome of H. pylori may modulate the action of virulence factors like CagA may prove useful in identification of persons for whom H. pylori eradication efforts would be most important. This review examines recent studies on interleukin-1β polymorphisms and H. pylori CagA variation with respect to their modulation of risk for gastric cancer.
Aspirin Use and Risk of Biliary Tract Cancer: A Population-Based Study in Shanghai, China
Authors: Liu Enju , Sakoda Lori C. , Gao Yu-Tang , Rashid Asif , Shen Ming-Chang , Wang Bing-Sheng , Deng Jie , Han Tian-Quan , Zhang Bai-He , Fraumeni Joseph F. , Hsing Ann W.
Published: September 2005

The association of gallbladder and bile duct cancers with gallstones, cholecystitis, and cholangitis suggest that chronic inflammation contributes to the carcinogenic process. However, the effect of nonsteroidal anti-inflammatory drugs, such as aspirin, on biliary tract cancer has not been well studied. In a population-based case-control study conducted in Shanghai, China, we examined the relationship between aspirin use and the risk of biliary disease. A total of 627 patients with biliary tract cancer, including cancers of the gallbladder (n = 368), extrahepatic bile duct (n = 191), and ampulla of Vater (n = 68); 1,037 patients with biliary stones; and 958 healthy adults were included in the study. Self-reported data on aspirin use was collected from study participants by in-person interview. The prevalence of aspirin use was low, with 5.7% of the population controls being regular users. After controlling for age, sex, education, and biliary stone status, aspirin use was associated with a reduced risk of gallbladder cancer [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.17-0.88]. An inverse relationship was also observed for frequency and duration of use and with younger age when starting use. In addition, there was a nonsignificant reduction in the risk of bile duct (OR, 0.48; 95% CI, 0.19-1.19) and ampullary cancers (OR, 0.22; 95% CI, 0.03-1.65) associated with aspirin use, whereas no clear association was seen with biliary stones (OR, 0.92; 95% CI, 0.59-1.44). Further studies of biliary tract cancer in other populations are needed to confirm these results and to elucidate the mechanisms that underlie the reduced risk associated with use of aspirin and possibly other nonsteroidal anti-inflammatory drugs.
GSTM1, GSTT1, andGSTP1Polymorphisms and Risk of Advanced Colorectal Adenoma
Authors: Moore Lee E. , Huang Wen-Yi , Chatterjee Nilanjan , Gunter Marc , Chanock Stephen , Yeager Meredith , Welch Bob , Pinsky Paul , Weissfeld Joel , Hayes Richard B.
Published: September 2005

Cigarette smoking is a risk factor for colon adenoma. The glutathione S-transferase enzymes are involved in the detoxification of carcinogenic compounds including those found in tobacco smoke, and thus, may be important modifiers of individual risk of developing this disease. We examined the prevalence of GSTM1 and GSTT1 gene deletions, and two GSTP1 polymorphisms in 772 cases with advanced colorectal adenomas (>1 cm, villous elements or high-grade dysplasia) of the distal colon (descending or sigmoid colon or rectum) and 777 sigmoidoscopy negative controls enrolled in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Epidemiologic data on smoking was collected by self-administered questionnaire and DNA was extracted from whole blood or buffy coat. For GSTM1 and GSTT1, we used a newly developed TaqMan-based assay capable of discriminating heterozygous (+/−) individuals from those with two active alleles (+/+) and homozygous deletions (−/−). For GSTP1, the I105V and the A114V substitutions were identified using end point 5′ nuclease assays (TaqMan). Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were determined using unconditional logistic regression, controlling for age, race, and gender. Advanced adenoma risk was increased in current/former smokers (OR, 1.4; 95% CI, 1.2-1.8). Risks were decreased in subjects with ≥1 inactive GSTM1 alleles (OR, 0.6; 95% CI, 0.4-0.9); and the association was independent of smoking status (P interaction = 0.59). Having ≥1 inactive GSTT1 allele was associated with increased risk among smokers (OR, 1.4; 95% CI, 1.1-1.9; Ptrend = 0.02) but not among never smokers (OR, 0.9; 95% CI, 0.6-1.3) and a significant interaction between smoking and genotype was observed (P interaction = 0.05). In summary, this is the first study to report associations between colorectal adenomas and GSTM1 wild-type and GSTT1 null allele among smokers. These findings only became apparent using a newly developed assay able to distinguish heterozygous from wild-type individuals. Our data provide evidence that phenotypic differences between these two groups exist.
Fruits, Vegetables, and Antioxidants and Risk of Gastric Cancer among Male Smokers
Authors: Nouraie Mehdi , Pietinen Pirjo , Kamangar Farin , Dawsey Sanford M. , Abnet Christian C. , Albanes Demetrius , Virtamo Jarmo , Taylor Philip R.
Published: September 2005

The effect of consumption of fruits, vegetables, and antioxidants on the incidence of gastric cancer is inconclusive. In this prospective cohort study, we report the association of dietary intake of fruits, vegetables, antioxidants, and baseline serum levels of antioxidants with subsequent incidence of gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). Participants of this study were 29,133 male smokers recruited into the α-Tocopherol, β-Carotene Cancer Prevention study between 1985 and 1988. At baseline, a self-administered food use questionnaire with 276 food items was used to assess dietary intake. Baseline serum samples were stored at −70°C. During a median follow-up of 12 years, 243 incident gastric adenocarcinomas (64 GCC and 179 GNCC) were diagnosed in this cohort, of whom 220 (57 GCC and 163 GNCC) had complete dietary information. For GCC, high dietary intake of retinol was protective [hazard ratio (HR), 0.46; 95% confidence interval (95% CI), 0.27-0.78], but high intake of α-tocopherol (HR, 2.06; 95% CI, 1.20-3.54) and γ-tocopherol (HR, 1.94; 95% CI, 1.13-3.34) increased risk. For GNCC, higher intakes of fruits (HR, 0.51; 95% CI, 0.37-0.71), vitamin C (HR, 0.60; 95% CI, 0.41-0.86), α-tocopherol (HR, 0.78; 95% CI, 0.55-1.10), γ-tocopherol (HR, 0.69; 95% CI, 0.49-0.96), and lycopene (HR, 0.67; 95% CI, 0.47-0.95) were protective. Our results suggest a difference in the effect of some of these exposures on GCC and GNCC. Tocopherols were associated with higher risk of GCC, whereas dietary intake of fruits, vitamin C, tocopherols, and lycopene seemed protective for GNCC.
Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Breast Cancer Risk
Authors: González-Zuloeta Ladd Angela M. , Arias Vásquez Alejandro , Sayed-Tabatabaei Fakhredin A. , Coebergh J.W. , Hofman Albert , Njajou Omer , Stricker Bruno , van Duijn Cornelia
Published: September 2005

Background: The renin-angiotensin system plays an important role in homeostasis and lately, its main effector, angiotensin II, has been attributed with angiogenic and growth factor actions in the breast tissue. Previous studies have shown that the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for the variability of ACE plasma concentrations. The use of ACE inhibitors and the ACE I/D polymorphism may be linked to breast cancer risk. In this study, we evaluate the relationship of the ACE I/D polymorphism with breast cancer risk in Caucasian postmenopausal women.

Methods: The ACE I/D polymorphism was genotyped in 4,117 women participants in the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted a logistic regression and survival analysis to assess the risk of breast cancer by the ACE genotype.

Results: The DD carriers showed a significantly increased risk of developing breast cancer when compared with the II carriers (odds ratio, 1.86; 95% confidence interval, 1.06-3.27; P = 0.03). This association remained after adjusting for other risk factors, including body mass index, age at menarche, age at menopause, hormone replacement therapy, and hypertension. Our survival analysis showed that the cancer-free survival was significantly reduced in DD compared with II carriers (hazard ratio, 1.80; 95% confidence interval, 1.07-3.01; P = 0.03).

Conclusions: Our results suggest that the ACE I/D polymorphism plays an important role in breast cancer risk and disease-free survival in Caucasian postmenopausal women.
Menstrual Cycle Characteristics and Incidence of Premenopausal Breast Cancer
Authors: Terry Kathryn L. , Willett Walter C. , Rich-Edwards Janet W. , Hunter David J. , Michels Karin B.
Published: September 2005

Background: Epidemiologic studies have indicated that menstrual cycle characteristics such as age at menarche and age at menopause are associated with breast cancer risk. Anovulation, which is more common with long or irregular cycles, has been hypothesized to reduce the incidence of breast cancer.

Methods: We analyzed data from the Nurses' Health Study II, a cohort of 116,671 female registered nurses ages 25 to 42 years at baseline. Information on menstrual cycle characteristics was assessed in 1989 and 1993, and incident cases of premenopausal breast cancer were ascertained through 2001.

Results: During 1,135,496 person-years of follow-up (1989-2001), 1,163 incident cases of invasive premenopausal breast cancer were diagnosed. Overall, women with long menstrual cycles at ages 18 to 22 years (>32 days or too irregular to estimate) did not experience a significantly lower breast cancer risk compared with women with normal cycle lengths (26-31 days) at that age [covariate-adjusted hazard ratio (HR), 0.92; 95% confidence interval (95% CI), 0.79-1.06]. Among women ages <40 years, those with menstrual cycles lasting >32 days or too irregular to estimate at ages 18 to 22 years had a decreased incidence of breast cancer (covariate-adjusted HR, 0.71; 95% CI, 0.53-0.97). Current menstrual cycle characteristics were not associated with breast cancer incidence.

Conclusion: Overall, longer or irregular cycles at ages 18 to 22 years or in early adulthood were not associated with reduced premenopausal breast cancer risk. However, longer menstrual cycles at ages 18 to 22 years were associated with a lower incidence of premenopausal breast cancer before age 40.
High Level of Correlation of Human Papillomavirus-16 DNA Viral Load Estimates Generated by Three Real-time PCR Assays Applied on Genital Specimens
Authors: Fontaine Julie , Gravitt Patti , Duh Lee-Min , Lefevre Jonas , Pourreaux Karina , Hankins Catherine , Coutlée François ,   The Canadian Women's HIV Study Group
Published: September 2005

Human papillomavirus-16 (HPV-16) viral load could be a biomarker predictive of the presence of high-grade cervical lesions. Recently, several real-time PCR assays have been developed to accurately measure HPV-16 viral load. However, results from various reports using these assays cannot be compared because interassay test correlation has not been documented. The variability of HPV-16 DNA quantitation was assessed by comparing three real-time PCR assays (HPV-16 L1, HPV-16 E6, and HPV-16 E6 PG) applied on 144 genital samples (125 cervicovaginal lavages and 19 specimens collected using vaginal tampons) obtained from 84 women (66 HIV seropositive and 18 HIV seronegative). Correlation was greater between the HPV-16 E6 assays [correlation coefficient (ρ) = 0.92] than between each E6 assay and HPV-16 L1 assay (ρ = 0.83 and 0.84, respectively). The median HPV-16 copies measured by HPV-16 E6 PG (14,609 HPV-16 copies/2 μL sample) and HPV-16 E6 (18,846 HPV-16 copies/2 μL) were similar (P = 0.27) but were both greater than the median HPV-16 copies measured with the L1 assay (4,124 HPV-16 copies/2 μL; P < 0.001). Correlations between HPV-16 E6 assays were similar for samples containing non-European (ρ = 0.93) or European (ρ = 0.95) variants. However, the correlation between HPV-16 L1 and HPV-16 E6 PG or HPV-16 E6 was lower for specimens containing non-European variants (ρ = 0.80 and 0.76, respectively) compared with specimens containing European variants (ρ > 0.85). HPV-16 DNA quantity estimated with the three assays was comparable although lower with the HPV-16 L1 assay. The level of correlation depended on viral polymorphism, viral load, and cervical disease status.
Polymorphisms of the Dopamine Receptor Gene DRD2 and Colorectal Cancer Risk
Authors: Gemignani Federica , Landi Stefano , Moreno Victor , Gioia-Patricola Lydie , Chabrier Amélie , Guino Elisabet , Navarro Matilde , Cambray Maria , Capellà Gabriel , Canzian Federico ,   the Bellvitge Colorectal Cancer Study Group
Published: September 2005

Sporadic colorectal cancer is considered a multifactorial disease in which multiple exposures interact with the individual genetic background resulting in risk modulation. Recent experimental data suggest a role of dopamine and dopamine receptors in the control of proliferation of the cells of colon and gastrointestinal tract. To investigate whether polymorphisms within dopamine receptors genes could have a role in modulating the risk of sporadic colorectal cancer, we did a case-control association study and genotyped 370 cases and 327 controls for seven single-nucleotide polymorphisms (SNP) of DRD2 (−141Cdel, 957T>C, TaqIB, TaqIA, 1412A>G, S311C, and 3208G>T) by a microarray-based technique. Three SNPs within DRD2 were associated with colorectal cancer, with a maximum odds ratio of 2.28 (95% confidence interval, 1.38-3.76) for carriers of the functional SNP −141Cdel. The haplotype which includes −141Cdel, together with the variants 957C and 1412G, shows an odds ratio of 2.86 (95% confidence interval, 1.58-5.18), as compared with the most frequent haplotype. The SNPs within DRD2 associated with colorectal cancer are known to be related to reduced levels of D2 dopamine receptor. Thus, our data point to a possible role of dopamine receptor DRD2 in modulating the risk of colorectal cancer. Future studies on dopamine receptor–mediated signal transduction may provide new insight into the mechanisms of colorectal cancer and suggest new therapeutic strategies.
Carbonyl Reductase Expression and Its Clinical Significance in Non–Small-Cell Lung Cancer
Authors: Takenaka Kazumasa , Ogawa Eiji , Oyanagi Hiroki , Wada Hiromi , Tanaka Fumihiro
Published: September 2005

Carbonyl reductase (CBR) is a cytosolic NADPH-dependent oxidoreductase metabolizing prostaglandins, steroids, quinines, and anthracycline antibiotics. Many experimental studies have shown that CBR plays important roles in the regulation of tumor progression, but clinical significance of CBR status remains unclear. Thus, we conducted a retrospective study on CBR mRNA expression in lung cancer. Tumor tissues obtained from 59 non–small-cell lung cancer patients were analyzed by quantitative real-time reverse transcription-PCR assay to reveal clinical significance of CBR expression. Angiogenesis was measured immunohistochemically as intratumoral microvessel density (IMVD) using anti-CD34 monoclonal antibody CD34-IMVD) and anti-CD105 monoclonal antibody (CD105-IMVD). CBR mRNA expression was significantly reduced along with progression of primary tumors (the mean CBR mRNA/GAPDH mRNA, 3.288 × 10−2 for pT1, 1.628 × 10−2 for pT2, and 1.175 × 10−2 for pT3-4 disease, respectively; P = 0.02). Moreover, CBR mRNA expression in tumor with nodal involvement seemed to be reduced as compared with that in tumor without nodal involvement (the mean CBR mRNA/GAPDH mRNA, 1.446 × 10−2 and 2.531 × 10−2, respectively), whereas the difference did not reach a statistical significance (P = 0.09). The mean CD105-IMVD for CBR-high tumor was 59.2, which was significantly lower than that for CBR-low tumor (130.6, P = 0.02), whereas no significant difference between the mean CD34-IMVDs for CBR-high tumor and CBR-low tumor was found. The 5-year survival rate of CBR-high patients was 68.3%, significantly higher than that of CBR-low patients (36.5%; P = 0.03). A multivariate analysis confirmed that CBR-high expression was a significant factor to predict a favorable prognosis (P = 0.04; relative risk, 0.39; 95% confidence interval, 0.16-0.98). Expression of CBR mRNA was a significant prognostic factor in non–small-cell lung cancer and was inversely associated with tumor progression and angiogenesis.
Long-term Cryoconservation and Stability of Vitamin C in Serum Samples of the European Prospective Investigation into Cancer and Nutrition
Authors: Jenab Mazda , Bingham Sheila , Ferrari Pietro , Friesen Marlin D. , Al-Delaimy Wael K. , Luben Robert , Wareham Nick , Khaw Kay-Tee , Riboli Elio
Published: September 2005

Plasma vitamin C level may be associated with risk of some chronic diseases. The rapid degradability of vitamin C in biological samples necessitates its stabilization with metaphosphoric acid or similar agents. However, in most cohort studies, prospectively collected biological samples are not treated with stabilizing agents before long-term frozen storage and it is not known whether vitamin C can be properly measured in such samples. The objective of this study was to determine the degree of vitamin C degradation in plasma samples stored without stabilization for 7 to 11 years at −196°C. Spearman's correlation coefficients indicate a moderate correlation between baseline and final plasma vitamin C levels in both men (r = 0.57, P < 0.0001) and women (r = 0.52, P < 0.0001). Samples were also categorized based on low or high baseline levels of plasma vitamin C, with the latter category showing the highest rate of loss per year of frozen storage in men (1.96 μmol/L, P value for difference <0.0001; percent loss 24.6%) and women (2.35 μmol/L, P value for difference <0.0001; percent loss 24.2%), as determined by multiple regression analysis adjusted for smoking status, age, and body mass index. In men, both baseline and final plasma vitamin C values were lower in smokers than never smokers, but for both men and women the rate of vitamin C loss during storage was not significantly different between smokers and never smokers. The results of this study show that vitamin C can be measured with reasonable reliability in plasma samples frozen for long periods of time without addition of any stabilizing agents.
The Relationship Between Student Smoking in the School Environment and Smoking Onset in Elementary School Students
Authors: Leatherdale Scott T. , Manske Steve
Published: September 2005

This study examined how perceptions of student smoking in the school environment and the actual smoking rate among senior students at a school are related to smoking onset. Multilevel logistic regression analysis was used to examine correlates of ever smoking in a sample of 4,286 grade 6 and 7 students from 57 elementary schools in Ontario, Canada. Students are at increased risk for smoking if they (a) often see students smoking near their school, (b) report that students at their school smoke where they are not allowed, and (c) attend a school with a relatively high senior student smoking rate. Each 1% increase in the smoking rate among grade 8 students increased the odds that a student in grades 6 or 7 was an ever smoker versus never smoker (odds ratio, 1.05; 95% confidence interval, 1.02-1.08). A low-risk student (no family or friends who smoke) was over twice as likely to try smoking if he/she attended a high-risk school. Prevention programs should target both at-risk schools and at-risk students, and strongly enforced policies preventing students from smoking on or near school property should be implemented.
Increased Risk of Cancer among Siblings of Long-term Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study
Authors: Friedman Debra L. , Kadan-Lottick Nina S. , Whitton John , Mertens Ann C. , Yasui Yutaka , Liu Yan , Meadows Anna T. , Robison Leslie L. , Strong Louise C.
Published: September 2005

We determined risk of cancer among first-degree relatives of 5-year survivors of childhood leukemia, lymphoma, central nervous system tumors, sarcomas, Wilms' tumor, and neuroblastoma. Subjects were 13,703 participants in the Childhood Cancer Survivor Study. Family history was collected on 56,759 first-degree relatives using a self-reported questionnaire. Incidence was compared with age- and sex-specific rates using the U.S. Surveillance, Epidemiology and End Results program. Siblings of the survivors had an increased risk of cancer [standardized incidence ratio (SIR), 1.5; 95% confidence interval (95% CI), 1.35-1.7]. Risk was elevated for siblings of probands of leukemia (SIR, 1.3; 95% CI, 1.0-1.6), Hodgkin's disease (SIR, 1.5; 95% CI, 1.2-1.9), non-Hodgkin's lymphoma (SIR, 1.8; 95% CI, 1.3-2.5), Wilms' tumor (SIR, 1.9; 95% CI, 1.2-3.2), soft tissue sarcoma (SIR, 1.5; 95% CI, 1.0-2.2), and bone tumors (SIR, 1.6; 95% CI, 1.2-2.2). Cancer risk was elevated in siblings (SIR, 2.4; 95% CI, 1.5-3.7) and offspring (SIR, 15.0; 95% CI, 5.3-42.9) of probands with second malignant neoplasms (SMN) compared with relatives of probands without SMNs. Siblings of probands with leukemia, Hodgkin's disease, neuroblastoma, and Wilms' tumor had elevated risks for the same malignancies. Parents had no increased risk (fathers' SIR, 0.7; 95% CI, 0.7-0.8; mothers' SIR, 0.9; 95% CI, 0.9-1.0). Seventy percent of siblings' cancers developed in adulthood. These findings suggest that familial cancer syndromes may be revealed as this cohort and family members age and with accrual of more offspring and subjects with SMNs.
Vitamin D and Calcium Intakes from Food or Supplements and Mammographic Breast Density
Authors: Bérubé Sylvie , Diorio Caroline , Mâsse Benoît , Hébert-Croteau Nicole , Byrne Celia , Côté Gary , Pollak Michael , Yaffe Martin , Brisson Jacques
Published: September 2005

Background: A better understanding of factors that affect breast density, one of the strongest breast cancer risk indicators, may provide important clues about breast cancer etiology and prevention. This study evaluates the association of vitamin D and calcium, from food and/or supplements, to breast density in premenopausal and postmenopausal women separately.

Methods: A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City, Canada, in 2001 to 2002, completed a food frequency questionnaire to assess vitamin D and calcium. Breast density from screening mammograms was assessed using a computer-assisted method. Associations between vitamin D or calcium and breast density were evaluated using linear regression models. Adjusted means in breast density were assessed according to the combined daily intakes of the two nutrients using generalized linear models.

Results: In premenopausal women, total intakes of vitamin D and calcium were inversely related to breast density (β = −1.4; P = 0.004 for vitamin D; β = −0.8; P = 0.0004 for calcium). In multivariate linear regression, simultaneous increments in daily total intakes of 400 IU vitamin D and 1,000 mg calcium were associated with an 8.5% (95% confidence interval, 1.8-15.1) lower mean breast density. The negative association between dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and vice versa. Among postmenopausal women, intakes of vitamin D and calcium were not associated with breast density.

Conclusion: These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower levels of breast density among premenopausal women. They suggest that increasing intakes of vitamin D and calcium may represent a safe and inexpensive strategy for breast cancer prevention.
Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families
Authors: Weitzel Jeffrey N. , Lagos Veronica , Blazer Kathleen R. , Nelson Rebecca , Ricker Charité , Herzog Josef , McGuire Colleen , Neuhausen Susan
Published: September 2005

Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown.

Methods: One hundred and ten unrelated probands ofHispanicorigin, with a personal or family history of breast and/orovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board–approved registry and underwent BRCA testing. Haplotype analyseswere done if BRCA mutations were observed in two or more unrelated probands.

Results: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses ofadditional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seenalmost exclusively in families with Latin American/Caribbean or Spanish ancestry.

Conclusion: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation wasprevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewishfounder haplotype.
Correlation of Human Papillomavirus Type 16 and Human Papillomavirus Type 18 E7 Messenger RNA Levels with Degree of Cervical Dysplasia
Authors: Scheurer Michael E. , Tortolero-Luna Guillermo , Guillaud Martial , Follen Michele , Chen Zhuo , Dillon Laura M. , Adler-Storthz Karen
Published: September 2005

Infection with certain types of human papillomavirus (HPV) is a necessary event in the development of cervical carcinoma; however, not all women who become infected with HPV will progress to cancer. Much is known about the molecular influence of HPV E6 and E7 proteins on the malignant transformation. Little is known about the additional factors needed to drive the process. Quantitative real-time PCR was used to quantitate mRNA expression of the E7 gene in women exhibiting normal epithelium, low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL). Prevalence of mRNA transcripts was lower among normal women (27%) than for women with LSIL (40%) and HSIL (37%). Mean levels ranged from 2.0 (ln scale per 20 ng cDNA) among normal women to 4.2 among those with HSIL, with a significant trend (P = 0.008). This trend was only significant for HPV 18 transcripts if separately analyzed by HPV type. The transcriptional activity of HPV 18 is higher than that of HPV 16 and increases with increasing level of dysplasia. This is in concert with the findings of other studies, and reinforces the notion that HPV 18 is a more aggressive viral type. Real-time PCR of viral transcripts could provide a more efficient method to analyze the oncogenic potential within cells from a cervical swab, thus providing a way to better screen women who may progress to higher grade lesions or invasive carcinoma from those who will spontaneously regress.
Tobacco Use and Stomach Cancer in Mizoram, India
Authors: Phukan Rup Kumar , Zomawia Eric , Narain Kanwar , Hazarika Nakul Chandra , Mahanta Jagadish
Published: September 2005

The incidence of stomach cancer in India is lower than that of any other country around the world. However, in Mizoram, one of the north-eastern state of India, a very high age-adjusted incidence of stomach cancer is recorded. A hospital-based case-control study was carried out to identify the influence of tobacco use on the risk of developing stomach cancer in Mizoram. Among the cases, the risk of stomach cancer was significantly elevated among current smokers [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.4-8.4] but not among ex-smokers. Higher risks were seen for meiziol (a local cigarette) smokers (OR, 2.2; 95% CI, 1.3-9.3). The increased risk was apparent among subjects who had smoked for ≥30 years. The increased risk was significant with 2-fold increase in risk among the subjects who smoked for ≥11 pack-years. The risk increased with increasing cumulative dose of tobacco smoked (mg). Tuibur (tobacco smoke–infused water), used mainly in Mizoram, was seemed to increased the risk of stomach cancer among current users in both univariate and multivariate models (OR, 2.1; 95% CI, 1.3-3.1). Tobacco chewer alone (OR, 2.6; 95% CI, 1.1-4.2) showed significant risk. Tobacco use in any form [smoking and smokeless (tuibur and chewing)] increased the risk of stomach cancer in Mizoram independently after adjusting for confounding variables.
Estrogen Metabolism–Related Genes and Breast Cancer Risk: The Multiethnic Cohort Study
Authors: Le Marchand Loïc , Donlon Timothy , Kolonel Laurence N. , Henderson Brian E. , Wilkens Lynne R.
Published: September 2005

Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk. We investigated the associations between breast cancer and sequence variants in several genes in the estradiol/estrone metabolism pathway (CYP1A1*2A, CYP1A2*1F, CYP1B1 Leu432Val, CYP3A4*1B, COMT Val158Met, SULT1A1Arg213His) as well as the Arg554Lys variant in AHR (a transcription factor for CYP1A1, CYP1A2, and CYP1B1) in a case-control study of 1,339 breast cancer cases and 1,370 controls nested in the Multiethnic Cohort Study. The Multiethnic Cohort Study is a large prospective study of men and predominantly postmenopausal women of Japanese, White, African American, Latino, and Native Hawaiian ancestry, residing in Hawaii and Los Angeles. We found no association between breast cancer and these polymorphisms, except for CYP1A2*1F which was inversely associated with risk. The odds ratio (95% confidence interval) for the AA, AC, and CC genotype was 1.0, 0.9 (0.7-1.0), and 0.7 (0.5-1.0), respectively (P for gene dosage effect = 0.03). This association seemed somewhat stronger for estrogen receptor (ER)/progesterone receptor (PR)–negative tumors than for ER/PR-positive tumors, and no statistically significant interaction with estrogen-related risk factors was detected. The findings provide no evidence for a role of COMT Val58Met, CYP1A1*2A, CYP3A4*1B, CYP1B1 Leu432Val, SULT1A1 Arg213His, and AHR Arg554Lys in breast cancer etiology. They also provide support for an inverse association between CYP1A2*1F and breast cancer, which is consistent with the observation of lower circulating estrogen levels in premenopausal women with the CC genotype in a previous study.
Folate Intake and Risk of Breast Cancer Characterized by Hormone Receptor Status
Authors: Zhang Shumin M. , Hankinson Susan E. , Hunter David J. , Giovannucci Edward L. , Colditz Graham A. , Willett Walter C.
Published: September 2005

Folate plays an important role in DNA methylation, and aberrant methylation of the estrogen receptor (ER) gene may be related to the loss of ER gene expression in breast tumors. Thus, deficient folate status has been hypothesized to be associated primarily with ER gene–negative breast tumors, but data relating folate intake to breast cancer risk according to ER status are sparse. We conducted a prospective cohort analysis of folate intake among 88,744 women in the Nurses' Health Study who completed a food frequency questionnaire in 1980 and every 2 to 4 years thereafter. During 20 years of follow-up, 2,812 ER+ and 985 ER− invasive breast cancer cases were documented. Higher total folate intake was significantly associated with lower risk of developing ER− but not ER+ breast cancer; the multivariable relative risks (RR) and 95% confidence intervals (95% CI) comparing the highest to the lowest quintile were 0.81 (0.66-0.99) for ER− tumors and 1.00 (0.89-1.14) for ER+ tumors. The inverse association between total folate intake and ER− breast cancer was mainly present among women consuming at least 15 g/d of alcohol (multivariable RR, 0.46; 95% CI, = 0.25-0.86; top versus bottom quintile). These findings support the hypothesis that higher folate intake reduces the risk of developing ER− breast cancer. Ensuring adequate folate intake seems particularly important for women at higher risk of breast cancer because of alcohol consumption.
Height, Age at Menarche, and Risk of Epithelial Ovarian Cancer
Authors: Jordan Susan J. , Webb Penelope M. , Green Adèle C.
Published: September 2005

Objective: We hypothesized that the hormonal changes of adolescence influence ovarian cancer risk particularly in younger women. We investigated this possibility by examining the relationship between ovarian cancer and adult height and age at menarche as both factors reflect pubertal hormonal levels.

Methods: Participants were a population-based sample of women with incident ovarian cancer (n = 794) and control women randomly selected from the Australian Electoral Roll (n = 855). The women provided comprehensive reproductive and lifestyle data during a standard interview.

Results: Although neither height nor age at menarche was significantly related to the risk of ovarian cancer overall, increasing height was associated with increasing risk of the subgroup of mucinous borderline ovarian cancer (odds ratio, 5.3; 95% confidence interval, 1.5-19.1 for women ≥175 cm compared with women <160 cm, Ptrend = 0.02). Similarly, later age at menarche was associated with increasing risk of mucinous borderline cancers (odds ratio, 3.8; 95% confidence interval, 1.3-11.4 for those with age at menarche ≥14 years compared with those <12 years, Ptrend = 0.003). Women with mucinous borderline cancers were significantly younger than the women diagnosed with invasive cancers (mean 44 versus 57 years; P < 0.0001).

Conclusions: Development of mucinous borderline ovarian cancers, predominantly diagnosed in women ages under 50 years, seems to be associated with age at menarche and attained adult height. These results are consistent with our original hypothesis that pubertal levels of reproductive hormones and insulin-like growth factor-I influence ovarian cancer risk in younger women.
Genetic Polymorphisms of GlutathioneS-Transferases and the Risk of Adult Brain Tumors: A Meta-analysis
Authors: Lai Rose , Crevier Louis , Thabane Lehana
Published: September 2005

Background: Studies investigating the association between genetic polymorphisms of glutathione S-transferases (GST) and risk of adult brain tumors have reported conflicting results. The rationale of this meta-analysis was to determine whether GST variants increase the susceptibility of adult brain tumors by pooling data.

Methods: Two investigators independently searched the HuGENet database, MEDLINE, EMBASE, conference articles, and manually reviewed bibliographies of retrieved articles. Papers were included if they were observational studies investigating the influence of GSTM1, GSTT1, GSTP1 I105V, or GSTP1 A114V on the development of adult brain cancers. Potential sources of heterogeneity between studies were explored in a meta-regression.

Results: We identified eight eligible studies, which included 1,630 cases of glioma, 245 cases of meningioma, and 7,151 controls. Using the random effects model, there was no association between any of the GST variants and the risk of glioma [overall odds ratio (OR), 1.08; 95% confidence interval (95% CI), 0.95-1.22]. Subgroup analyses also showed no relationship between GST variants and histopathologic groups; the overall ORs were 1.13 (95% CI, 0.88-1.43) for high-grade glioma and 1.08 (95% CI, 0.76-1.55) for low-grade glioma. A random effects meta-regression suggested that the use of in-hospital controls produced larger effect estimates in glioma than the use of population controls (overall OR, 1.30; 95% CI, 1.03-1.65). The T1 null genotype was significantly associated with a risk of meningioma (OR, 1.95; 95% CI, 1.02-3.76), but the M1 variant was not.

Conclusion: This study did not suggest any relationship between GST variants and risks of glioma; the T1 null genotype may influence the susceptibility of meningioma, but larger studies are needed to substantiate this relationship.
Fruits, Vegetables, and hMLH1 Protein–Deficient and –Proficient Colon Cancer: The Netherlands Cohort Study
Authors: Wark Petra A. , Weijenberg Matty P. , van 't Veer Pieter , van Wijhe Gerda , Lüchtenborg Margreet , van Muijen Goos N.P. , de Goeij Anton F.P.M. , Goldbohm R. Alexandra , van den Brandt Piet A.
Published: September 2005

Background: Clinical and pathologic differences exist between colon carcinomas deficient and proficient in the mismatch repair protein hMLH1. Animal and in vitro studies suggest that fruits, vegetables, folate, and antioxidants are associated with colonic expression of mismatch repair genes.

Methods: Associations between consumption of fruits and vegetables and hMLH1 protein–deficient and –proficient colon cancer were evaluated in the Netherlands Cohort Study on diet and cancer using a case-cohort approach. A self-administered food frequency questionnaire was completed, in 1986, by 120,852 individuals ages 55 to 69 years. Using immunohistochemistry, hMLH1 protein expression was assessed in colon cancer tissue obtained from 441 patients who were identified over 7.3 years of follow-up excluding the initial 2.3 years. Incidence rate ratios (RR) were estimated for hMLH1 protein–deficient and –proficient colon cancer.

Results: hMLH1 protein expression was absent in 54 tumors (12.2%) and present in 387 tumors. Fruit consumption was associated with hMLH1 protein–deficient colon cancer [highest versus lowest tertile, RR, 0.46; 95% confidence interval (95% CI), 0.23-0.90; Ptrend = 0.029] but not with hMLH1 protein–proficient tumors (highest versus lowest tertile, RR, 1.03; 95% CI, 0.78-1.35; Ptrend = 0.81). Total consumption of vegetables was not associated with either type of tumor (hMLH1 protein deficient: RR, 0.86; 95% CI, 0.45-1.65; Ptrend = 0.67; hMLH1 protein proficient: RR, 0.94; 95% CI, 0.72-1.23; Ptrend = 0.72). No associations were observed for folate, fiber, antioxidants, or subgroups of vegetables.

Conclusion: These analyses indicate that an inverse association between consumption of fruits and colon cancer may be confined to the subgroup of tumors with a deficient mismatch repair system.
Sulindac Inhibits β-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients
Authors: Koornstra Jan J. , Rijcken Fleur E.M. , Oldenhuis Corina N.A.M. , Zwart Nynke , van der Sluis Tineke , Hollema Harry , deVries Elisabeth G.E. , Keller Josbert J. , Offerhaus Johan A. , Giardiello Francis M. , Kleibeuker Jan H.
Published: September 2005

Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-β-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, β-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, β-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and sulindac. Intensity of membranous β-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits β-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.