Cancer Epidemiology Biomarkers & Prevention recent issues

Cancer Survivorship Research: Opportunities and Future Needs for Expanding the Research Base

Bhatia, S., Robison, L. L. — 2008-07-15

Aspirin is Clinically Effective in Chemoprevention of Colorectal Neoplasia: Point

Leshno, M., Moshkowitz, M., Arber, N. — 2008-07-15

Aspirin Should Not Be Promoted for Colon Cancer Prevention: Counterpoint

Sandler, R. S. — 2008-07-15

Use of Common Medications and Breast Cancer Risk

Moysich, K. B., Beehler, G. P., Zirpoli, G., Choi, J.-Y., Baker, J. A. — 2008-07-15

Prescription and over-the-counter medications are widely used in the United States and many western countries. More than two-thirds of women ages >45 years, who are at greatest risk for breast cancer, take prescription medication. In light of the ubiquitous nature of medication use and the fact that breast cancer remains the most common cancer in women, research on the role of medication use in breast cancer etiology is warranted. We summarize the epidemiologic evidence on the association between breast cancer risk and use of common medications, including antibiotics, antidepressants, statins, antihypertensives, and nonsteroidal anti-inflammatory drugs. Overall, there is little evidence that would implicate the use of antibiotics, antidepressants, statins, and antihypertensives in the etiology of breast cancer. Although several prospective studies and a randomized low-dose aspirin chemoprevention trial have not shown lower risk of breast cancer among aspirin users, most studies that have examined the potential chemoprotective effect of nonsteroidal anti-inflammatory drugs have shown significant risk reductions for regular and prolonged use of these drugs. The existing literature on the role of medication use in breast carcinogenesis is complicated. Interpretation of the evidence is hampered due to major methodologic differences across studies, including exposure assessment, exposure classification, and adjustment for potential confounding variables. These differences largely stem from the fact that the majority of articles on this topic represent secondary data analyses from studies with inadequate information on exposure or confounders. Thus, future epidemiologic studies specifically designed to study these ubiquitous and biologically plausible exposures are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1564–95)

Diet, Autophagy, and Cancer: A Review

Singletary, K., Milner, J. — 2008-07-15

A host of dietary factors can influence various cellular processes and thereby potentially influence overall cancer risk and tumor behavior. In many cases, these factors suppress cancer by stimulating programmed cell death. However, death not only can follow the well-characterized type I apoptotic pathway but also can proceed by nonapoptotic modes such as type II (macroautophagy-related) and type III (necrosis) or combinations thereof. In contrast to apoptosis, the induction of macroautophagy may contribute to either the survival or death of cells in response to a stressor. This review highlights current knowledge and gaps in our understanding of the interactions among bioactive food constituents, autophagy, and cancer. Whereas a variety of food components including vitamin D, selenium, curcumin, resveratrol, and genistein have been shown to stimulate autophagy vacuolization, it is often difficult to determine if this is a protumorigenic or antitumorigenic response. Additional studies are needed to examine dose and duration of exposures and tissue specificity in response to bioactive food components in transgenic and knockout models to resolve the physiologic implications of early changes in the autophagy process. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1596–610)

A Systematic Review of the Prevalence and Attribution of Human Papillomavirus Types among Cervical, Vaginal, and Vulvar Precancers and Cancers in the United States

Insinga, R. P., Liaw, K.-L., Johnson, L. G., Madeleine, M. M. — 2008-07-15

Objectives: To describe prevalence and estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal, and vulvar precancers and cancers.

Methods: U.S. studies reporting HPV typing for cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN) and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had PCR testing data for ≥10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types.

Results: Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were CIN 1 (HPV 16/66; 15.3%), CIN 2/3 (HPV 16/31; 61.9%), cervical cancer (HPV 16/18; 79.2%), VIN 1 (HPV 6/11; 41.7%), VIN 3 (HPV 16/18; 84.0%), vulvar cancer (HPV 16/33; 55.5%), VaIN 3 (HPV 16/18; 65.1%), and vaginal cancer (HPV 16/18; 72.7%).

Conclusions: The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar, and vaginal neoplasias and by grade of disease. Adjustment for the presence of multitype HPV infections can have an important effect on the estimated attribution of HPV types to disease, particularly for types other than HPV 16. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1611–22)

Colorectal Cancer Test Use from the 2005 National Health Interview Survey

2008-07-15

Background: Screening is effective in reducing colorectal cancer mortality. Recommended colorectal cancer screening options include a home fecal occult blood test (FOBT) or colorectal endoscopy (sigmoidoscopy or colonoscopy). Past surveys have indicated that colorectal cancer screening prevalence in the United States is low. The purpose of this analysis was to determine the prevalence of colorectal cancer test use in the United States by various factors and to examine reasons for not having a colorectal cancer test.

Methods: Data on respondents ages ≥50 years from the 2005 National Health Interview Survey (n = 13,269) were analyzed. The proportion of the U.S. population that had home FOBT within the past year or endoscopy within the past 10 years was examined by sociodemographic, health-care access, and other health-related factors. Reported reasons for not having FOBT or endoscopy were also analyzed.

Results: The age-standardized proportion of respondents who reported FOBT within the past year and/or endoscopy within the past 10 years was 50.0% [95% confidence interval (95% CI), 48.8-51.2]. Colorectal cancer testing rates were particularly low among people without health-care coverage (24.1%; 95% CI, 19.2-29.7) or without a usual source of health care (24.7%; 95% CI, 20.8-29.0). The most commonly reported reason for not having a colorectal cancer test was "never thought about it."

Conclusions: In 2005, about half of Americans ages ≥50 years did not have appropriate colorectal cancer testing. Increased efforts to expand health-care coverage or to provide colorectal cancer tests to people without health-care coverage are needed to increase colorectal cancer screening. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1623–30)

An Object Lesson: Source Determines the Relations That Trait Anxiety, Prostate Cancer Worry, and Screening Fear Hold with Prostate Screening Frequency

Consedine, N. S., Adjei, B. A., Ramirez, P. M., McKiernan, J. M. — 2008-07-15

Fears regarding prostate cancer and the associated screening are widespread. However, the relations between anxiety, cancer worry, and screening fear and screening behavior are complex, because anxieties stemming from different sources have different effects on behavior. In differentiating among anxieties from different sources (trait anxiety, cancer worry, and screening fear), we expected that cancer worry would be associated with more frequent screening, whereas fear of screening would be associated with less frequent screening. Hypotheses were tested in a sample of 533 men (ages 45-70 years) recruited using a stratified cluster-sampling plan. Men provided information on demographic and structural variables (age, education, income, marital status, physician discussion of risk and screening, access, and insurance) and completed a set of anxiety measures (trait anxiety, cancer worry, and screening fear). As expected, two-step multiple regressions controlling for demographics, health insurance status, physician discussion, and health-care system barriers showed that prostate-specific antigen and digital rectal examination frequencies had unique associations with cancer worry and screening fear. Specifically, whereas cancer worry was associated with more frequent screening, fear of screening was associated with less frequent screening at least for digital rectal examination; trait anxiety was inconsistently related to screening. Data are discussed in terms of their implications for male screening and the understanding of how anxiety motivates health behaviors. It is suggested that understanding the source of anxiety and the manner in which health behaviors such as cancer screenings may enhance or reduce felt anxiety is a likely key to understanding the associations between anxiety and behavioral outcomes. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1631–9)

Racial/Ethnic Disparities in the Use of Nicotine Replacement Therapy and Quit Ratios in Lifetime Smokers Ages 25 to 44 Years

2008-07-15

We examined racial/ethnic variations in the use of nicotine replacement therapy (NRT) and quit ratios among Caucasian, African American, Asian, and Latino lifetime smokers ages 25 to 44 years. We conducted cross-sectional analyses using data from individuals (n = 27,031) screened for enrollment in the Collaborative Study of the Genetics of Nicotine Dependence. Participants were randomly sampled from three Midwestern metropolitan areas using Health Maintenance Organization membership lists in Detroit, MI and Minneapolis, MN and a driver’s license registry in St. Louis, MO from March 2003 to August 2005. A telephone survey collected information on smoking history, previous quit attempts, and sociodemographic characteristics. Among lifetime smokers (n = 9,216), univariate analysis indicated that African Americans (22%) and Latinos (22%) were significantly less likely to report having ever used NRT for smoking cessation than Caucasians (31%). Asians (22%) also reported lower rates of using NRT than Caucasians, but this difference was marginally significant (P = 0.06). These disparities persisted in multivariate analysis for African Americans [adjusted odds ratio (OR), 0.76; 95% confidence interval (95% CI), 0.63-0.91; P < 0.01] but not for Latinos (adjusted OR, 0.76; 95% CI, 0.54-1.06; P = 0.11) or Asians (adjusted OR, 0.98; 95% CI, 0.60-1.60; P = 0.95). As measured by the quit ratio, African Americans (35%) were less likely to have quit smoking than Caucasians (52%). This disparity persisted in multivariate logistic regression (adjusted OR, 0.66; 95% CI, 0.56-0.78; P < 0.001). Asian and Latino smokers were as likely as Caucasians to report smoking cessation. Future prospective studies are needed to assess whether lower utilization of cessation treatments such as NRT contribute to the observed disparity in quit ratios for African Americans. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1640–7)

Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma

Jiang, N. Y., Woda, B. A., Banner, B. F., Whalen, G. F., Dresser, K. A., Lu, D. — 2008-07-15

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Sp1 is a sequence-specific DNA binding protein that is important in the transcription of a number of regulatory genes involved in cancer cell growth, differentiation, and metastasis. In this study, we investigated Sp1 expression in pancreatic ductal adenocarcinoma and its association with clinical outcome. We studied 42 patients with primary pancreatic adenocarcinoma. The expression of Sp1 in pancreatic adenocarcinoma was evaluated by immunohistochemical staining. All 42 patients had clinical follow-up information and were evaluated for survival. Sp1 protein was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. These tumors all developed metastasis, whereas none of the primary tumors without lymph node metastasis showed Sp1 overexpression. Statistically, Sp1 overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.036, and P < 0.0001, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without Sp1 overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.002). The 5-year overall survival rate was 19% in patients with Sp1 overexpression, compared with 55% in patients without Sp1 overexpression. The median survival was only 13 months for patients with Sp1 overexpression, compared with 65 months for patients without Sp1 overexpression. In conclusion, Sp1 is a new biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. It can be used at initial diagnosis of pancreatic adenocarcinoma to identify patients with an increased probability of cancer metastasis and much shortened overall survival. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1648–52)

Human Aflatoxin Albumin Adducts Quantitatively Compared by ELISA, HPLC with Fluorescence Detection, and HPLC with Isotope Dilution Mass Spectrometry

2008-07-15

Essential to the conduct of epidemiologic studies examining aflatoxin exposure and the risk of heptocellular carcinoma, impaired growth, and acute toxicity has been the development of quantitative biomarkers of exposure to aflatoxins, particularly aflatoxin B₁. In this study, identical serum sample sets were analyzed for aflatoxin-albumin adducts by ELISA, high-performance liquid chromatography (HPLC) with fluorescence detection (HPLC-f), and HPLC with isotope dilution mass spectrometry (IDMS). The human samples analyzed were from an acute aflatoxicosis outbreak in Kenya in 2004 (n = 102) and the measured values ranged from 0.018 to 67.0, nondetectable to 13.6, and 0.002 to 17.7 ng/mg albumin for the respective methods. The Deming regression slopes for the HPLC-f and ELISA concentrations as a function of the IDMS concentrations were 0.71 (r² = 0.95) and 3.3 (r² = 0.96), respectively. When the samples were classified as cases or controls, based on clinical diagnosis, all methods were predictive of outcome (P < 0.01). Further, to evaluate assay precision, duplicate samples were prepared at three levels by dilution of an exposed human sample and were analyzed on three separate days. Excluding one assay value by ELISA and one assay by HPLC-f, the overall relative SD were 8.7%, 10.5%, and 9.4% for IDMS, HPLC-f, and ELISA, respectively. IDMS was the most sensitive technique and HPLC-f was the least sensitive method. Overall, this study shows an excellent correlation between three independent methodologies conducted in different laboratories and supports the validation of these technologies for assessment of human exposure to this environmental toxin and carcinogen. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1653–7)

High Excretion of Etheno Adducts in Liver Fluke-Infected Patients: Protection by Praziquantel against DNA Damage

2008-07-15

Chronic infection by Opisthorchis viverrini (OV) is a strong risk factor for developing cholangiocarcinoma (CCA). To clarify the involvement of oxidative stress and lipid peroxidation (LPO)–derived DNA damage, the excretion of LPO-derived etheno DNA adducts was measured in urine samples collected from healthy volunteers and OV-infected Thai subjects. 1,N⁶-etheno-2'-deoxyadenosine (dA) and 3,N⁴-etheno-2'-deoxycytidine (dC) levels were quantified by immunoprecipitation/high-performance liquid chromatography/fluorescence detection and ³²P-postlabeling TLC. Excreted etheno adduct levels were related to indicators of inflammatory conditions [malondialdehyde (MDA) and nitrate/nitrite levels in urine and plasma alkaline phosphatase (ALP) activity]. Mean dA and dC levels were 3 to 4 times higher in urine of OV-infected patients; MDA, nitrate/nitrite, and ALP were also increased up to 2-fold. MDA and ALP were positively related to dA excretion. Two months after a single dose of the antiparasitic drug Praziquantel, dA and dC concentrations in urine of OV-infected subjects were decreased; MDA, nitrate/nitrite, and ALP were concomitantly lowered. We conclude that chronic OV infection through oxidative/nitrative stress leads to increased urinary excretion of the etheno-bridged deoxyribonucleosides, reflecting high LPO-derived DNA damage in vivo. These promutagenic DNA etheno adducts in bile duct epithelial cells may increase the risk of OV-infected patients to later develop CCA. Urinary dA and dC levels should be explored (a) as noninvasive risk markers for developing opisthorchiasis-related CCA and (b) as promising biomarkers to assess the efficacy of preventive and therapeutic interventions. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1658–64)

Successful Coordination and Execution of Nontherapeutic Studies in a Cooperative Group Setting: Lessons Learned from Children's Oncology Group Studies

2008-07-15

The immense progress made in childhood cancer survival has been due to the systematic and efficient conduct of large multicenter therapeutic trials, using the infrastructure developed by national cooperative groups. These therapeutic trials have been successful, in part due to the high participation rates by the participating member institutions. However, participation in nontherapeutic trials in the cooperative group setting has lagged behind that of therapeutic trials for a variety of reasons, such as lack of institutional resources, leading to low priority given to such activities. The purpose of this report is to share some of the methods developed and successfully implemented by a coordinating center (City of Hope National Medical Center) to maximize institutional participation and patient enrollment and to standardize data collection and quality control, in order to ensure the successful execution of two large, extramurally funded, cooperative group nontherapeutic studies. To date, over 175 institutions have obtained regulatory approval for the protocols showcased here, accrual has been on target, and completeness and quality of the collected data have been excellent. The successful execution of these nontherapeutic studies shows the advantages of diverse study publicity techniques, detailed standardized operating procedures, and effective utilization of technological resources. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1665–73)

Increases in Serum Estrone Sulfate Level Are Associated with Increased Mammographic Density during Menopausal Hormone Therapy

2008-07-15

Background: Menopausal hormone therapy increases mammographic density. We determined whether increases in serum estrone sulfate (E₁S) levels during menopausal hormone therapy predict increased mammographic density.

Methods: We measured percent mammographic density and serum E₁S levels in 428 participants of the Postmenopausal Estrogen/Progestin Interventions study who were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg alone, CEE + daily medroxyprogesterone acetate (MPA) 2.5 mg, CEE + cyclical MPA (10 mg days 1-12 per 28-day cycle), or CEE + cyclical micronized progesterone (10 mg days 1-12). Serum E₁S levels were determined by RIA. Information about covariates was determined by annual questionnaire. Using linear regression, we determined the association between change in E₁S level from baseline to 12 months and change in percent mammographic density (by semiquantitative interactive threshold method).

Results: After controlling for baseline mammographic density, age, body mass index, alcohol intake, parity, smoking, ethnicity, physical activity, and age at first pregnancy, mammographic density increased by 1.3% for every 1 ng/mL increase in E₁S level (P < 0.0001). The association between change in E₁S level and change in mammographic density differed by treatment group (greater effect in CEE + cyclical MPA group versus CEE group; P = 0.05). After controlling for treatment group, change in the ratio of E₁S to E₁ was also positively associated with change in mammographic density.

Conclusions: Increases in serum E₁S levels during menopausal hormone therapy are associated with increases in mammographic density. The relative contribution of E₁S and E₁ to stimulation of breast tissue awaits further elucidation. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1674–81)

Testing a Multigene Signature of Prostate Cancer Death in the Swedish Watchful Waiting Cohort

2008-07-15

Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1682–8)

Limits of Detection of Chemopreventive Efficacy: Karyometry of Skin Biopsies

2008-07-15

Objective: This study was designed to establish estimates of the smallest effects due to chemopreventive intervention detectable by karyometry in skin biopsies.

Methods: Estimates of the smallest change of statistical significance and estimates of the power of the test were derived for several key features descriptive of the distribution of nuclear chromatin. Results from triplicate biopsies from the same case were used to provide estimates of the within-case, biopsy-to-biopsy variance.

Results: Generally, a change in feature value due to chemopreventive intervention can be statistically secured when it amounts to 5% to 10%. In clinical trials where matched baseline and end of study biopsies from the same cases are available, paired comparison ANOVA can detect a 2% change on samples of 25 cases. Establishing efficacy in individual cases requires a change in feature values on the order of 10% to 15%.

Conclusions: Karyometry provides a sensitive, quantitative method for the assessment of efficacy of chemoprevention. The effects of within-case, biopsy-to-biopsy variance need to be considered only in the evaluation of individual cases and are on the order of 5% in skin biopsies. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1689–95)

Effect of Raloxifene on Mammographic Density and Breast Magnetic Resonance Imaging in Premenopausal Women at Increased Risk for Breast Cancer

2008-07-15

Background: Mammographic density is a risk factor for breast cancer. Mammographic density and breast magnetic resonance imaging (MRI) volume (MRIV) assess the amount of fibroglandular tissue in the breast. Mammographic density and MRIV can be modulated with hormonal interventions, suggesting that these imaging modalities may be useful as surrogate endpoint biomarkers for breast cancer chemoprevention trials. We evaluated the effect of raloxifene on mammographic density and MRIV in premenopausal women at increased risk for breast cancer.

Methods: Mammograms and MRI were obtained at baseline and after 1 and 2 years of 60 mg raloxifene by mouth daily for 27 premenopausal women. Mammographic percent dense area was calculated using a semiquantitative thresholding technique. T₁-weighted spoiled gradient-echo MRI with fat suppression was used to determine breast MRIV using a semiautomatic method. Mean change in mammographic density and median change in MRIV were assessed by the Wilcoxon signed-rank test.

Results: No significant change in mammographic density was seen after treatment with raloxifene. Mean change after 1 year was 1% [95% confidence interval (95% CI), –3 to +5] and after 2 years was 1% (95% CI, –2 to +5). MRIV decreased on raloxifene. Median relative change in MRIV after 1 year was -17% (95% CI, -28 to -9; P = 0.0017) and after 2 years was -16% (95% CI, -31 to -4; P = 0.0004).

Conclusions: In high-risk premenopausal women, mammographic density did not change on raloxifene, whereas MRIV significantly declined. Our findings suggest that MRIV is a promising surrogate biomarker in premenopausal women at increased risk for breast cancer and should be investigated further in breast cancer prevention trials. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1696–701)

Association of Aryl Hydrocarbon Receptor Gene Polymorphisms and Urinary 1-Hydroxypyrene in Polycyclic Aromatic Hydrocarbon-Exposed Workers

2008-07-15

Polycyclic aromatic hydrocarbons (PAH) in coke oven emissions could cause lung cancer in human. Individual's genotype of the metabolic enzymes and early biological changes were known to be associated with the susceptibility of cancer development. Knowledge of metabolic gene polymorphisms, which affect on the urinary 1-hydroxypyrene (1-OHP), could benefit us in understanding the interindividual difference in the mechanism of PAH-induced carcinogenesis. In this study, we investigated the association of aryl hydrocarbon receptor (AhR) gene polymorphisms and urinary 1-OHP. One hundred forty-seven workers exposed to PAH and 69 nonexposure workers were recruited. Seven tagging single nucleotide polymorphisms in AhR gene were selected by pariwise r² method and minor allele frequency cutoff of 0.05 from Chinese genotype data in HapMap project. These seven tagging single nucleotide polymorphisms were genotyped by PCR-based methods. Multivariate analysis of covariance revealed that the levels of 1-OHP in PAH-exposed workers carrying genotype CT were lower than workers carrying wild genotype TT at loci rs10250822 and rs2282885 of AhR gene (P = 0.032 and 0.044, respectively). In PAH-exposed workers, the urinary 1-OHP levels showed a linear correlation (P_trend = 0.041) with the genotypes at locus rs2282885, especially in low and moderate exposure groups. In contrast, no significant association was found between urinary 1-OHP level and AhR genotypes among nonexposed workers. Our findings indicated that polymorphisms of AhR gene were associated with the level of 1-OHP among PAH-exposed workers, suggesting that AhR-mediated signaling might contribute to individual susceptibility to PAH exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1702–8)

Breast Density Assessment in Adolescent Girls Using Dual-Energy X-ray Absorptiometry: A Feasibility Study

Shepherd, J. A., Malkov, S., Fan, B., Laidevant, A., Novotny, R., Maskarinec, G. — 2008-07-15

Breast density, the radiographically opaque fraction of the breast in a mammogram, is one of the strongest biomarkers of breast cancer risk. However, younger populations do not typically have mammograms due to radiation concerns. This study explored a commercially available dual-energy X-ray absorptiometer (DXA) system as a low-dose method to measure breast fibroglandular density in adolescent girls. Eighteen girls (13-14 years old) indicated their breast development according to Tanner and underwent three dedicated DXA scans, two of their left and one of their right breasts. Total projected breast area was manually delineated on each image and percent fibroglandular volume density (%FGV), absolute fibroglandular volume (FGV), total breast area, and volume were computed. It was possible to image breasts representing all five Tanner stages; %FGV ranged from 31.9% to 92.2% with a mean of 71.1 ± 14.8%, whereas FGV ranged from 80 to 270 cm³ with a mean of 168 ± 54 cm³. Left and right breast %FGV were highly correlated (r_p = 0.97, P < 0.0001) and of the same magnitude (P = 0.18). However, left total volume and FGV were larger than the right by 38 cm³ (P = 0.04) and 19 cm³ (P = 0.02), respectively. Total volume and FGV increased by Tanner stage, whereas %FGV did not. Our method had excellent precision for %FGV and moderate precision for FGV (root mean square SDs of 2.4% and 16.6 cm³). These pilot data indicate that dedicated DXA breast scans may be useful in studies exploring breast density in girls. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1709–13)

No Reduction in C-Reactive Protein following a 12-Month Randomized Controlled Trial of Exercise in Men and Women

2008-07-15

Low-grade systemic inflammation is suggested to play a role in the development of several chronic diseases including cancer. Higher levels of physical activity and lower adiposity have been associated with reduced levels of markers of systemic inflammation, such as C-reactive protein (CRP); however, reductions in CRP have not been consistently observed in randomized controlled trials of exercise.

Purpose: To examine the effect of a 12-month aerobic exercise intervention on CRP levels in men and women.

Methods: One hundred two men and 100 women, sedentary and of ages 40 to 75 years, with mean body mass index (BMI) of 29.9 and 28.7 kg/m², respectively, were randomly assigned to a 12-month moderate-to-vigorous aerobic exercise intervention (6 d/wk, 60 min/d, 60-85% maximum heart rate) or control group. Fasting blood samples were collected at baseline and at 12 months. CRP levels were measured by high-sensitivity latex-enhanced nephelometry.

Results: At baseline, CRP was 1.16 and 2.11 mg/L for men and women, respectively, and CRP was correlated with percent body fat (r = 0.48, P ≤0.001), BMI (r = 0.37, P ≤ 0.001), and aerobic fitness (r = –0.49, P ≤ 0.001). No intervention effects were observed for CRP in men or women, or when stratified by baseline BMI (<30 versus ≥30 kg/m²), baseline CRP (<3 versus ≥3 mg/L), or change in body weight, body composition, or aerobic fitness.

Conclusion: A 12-month moderate-to-vigorous aerobic exercise intervention did not affect CRP levels in previously sedentary men or women with average-risk CRP values at baseline. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1714–8)

Serum Insulin-Like Growth Factor-I and Platelet-Derived Growth Factor as Biomarkers of Breast Cancer Prognosis

Pasanisi, P., Venturelli, E., Morelli, D., Fontana, L., Secreto, G., Berrino, F. — 2008-07-15

Epidemiologic studies have shown that growth factors and inflammatory mechanisms may affect breast cancer risk and prognosis. The present analysis on 110 postmenopausal breast cancer patients tested if serum insulin-like growth factor I (IGF-I), platelet-derived growth factor (PDGF), fructosamine, and C-reactive protein, a serum marker of inflammation, are associated with breast cancer relapse. The risk of adverse events after 5.5 years of follow-up was examined by Cox proportional hazards modeling, controlling for hormone receptor status, stage at diagnosis, and for body weight and serum testosterone level, which were known to significantly affect prognosis. PDGF and, to a lesser extent, IGF-I were positively but not significantly associated with the risk of breast cancer recurrence. By combining PDGF and IGF-I, however, the adjusted hazard ratio of recurrence among the women with both PDGF and IGF-I levels > their median values (respectively, 9.3 and 174.4 ng/mL) was 6.4 (95% confidence interval, 1.5-26.7) compared with the women with PDGF and IGF-I levels ≤ their median values. Fructosamine and C-reactive protein were not associated with recurrences. The results suggest that PDGF may be an important prognostic factor for breast cancer and that IGF-I may increase the risk of recurrence in the presence of high PDGF levels. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1719–22)

Breast Cancer Risk and Hormone Receptor Status in Older Women by Parity, Age of First Birth, and Breastfeeding: A Case-Control Study

2008-07-15

Background: Early age at first birth and multiparity reduce the risk of estrogen receptor-progesterone receptor (ERPR)–positive breast cancer, whereas breastfeeding reduces the risk of both ERPR-positive and ERPR-negative cancers.

Methods: We used multivariable logistic regression analysis to investigate whether age at first birth (<25 or ≥25 years) and breastfeeding (ever/never) modify the long-term effect of parity on risk of ERPR-positive and ERPR-negative cancer using 1,457 incident breast cancer cases and 1,455 controls ages ≥55 years who participated in the Women's Contraceptive and Reproductive Experiences Study.

Results: Women who gave birth before age 25 years had a 36% reduced risk of breast cancer compared with nulligravida that was not observed for women who started their families at an older age (P_{heterogeneity} = 0.0007). This protective effect was restricted to ERPR-positive breast cancer (P_{heterogeneity} = 0.004). Late age at first birth increased the risk of ERPR-negative cancers.

Additional births reduced the risk of ERPR-positive cancers among women with an early first birth (P_trend = 0.0001) and among women who breastfed (P_trend = 0.004) but not among older mothers or those who never breastfed. In women with a late first birth who never breastfed, multiparity was associated with increased risk of breast cancer.

Conclusions: These findings suggest that the effect of parity on a woman's long-term risk of breast cancer is modified by age at first full-term pregnancy and possibly by breastfeeding. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1723–30)

Human Papillomavirus Infection in Ulaanbaatar, Mongolia: A Population-Based Study

2008-07-15

Data on human papillomavirus (HPV) and cervical cancer burden in Central Asia are scarce. To investigate HPV infection in Ulaanbaatar, the capital of Mongolia, we obtained cervical cell specimens from a population of 969 women ages 15 to 59 years. DNA of 44 HPV types was detected using a GP5+/6+ PCR-based assay. Seropositivity for L1 proteins of HPV 16, 18, 31, 33, 45, 52, and 58 was assessed using multiplex HPV serology. Cytologic abnormalities were detected in 127 women (13.1%), among whom 6 cervical intraepithelial neoplasia grade 3 and 2 invasive cervical cancers were diagnosed. Overall HPV DNA prevalence was 35.0%, being highest (48.5%) in women ages <25 years. High-risk types were detected in 24.5% of women. HPV DNA prevalence declined with age but remained >25% in all age groups. HPV seroprevalence was also very high (38.0%) and increased steadily from 33.2% to 48.9% in women ages <25 and 50 to 59 years, respectively. However, the proportion of women positive for both HPV markers of any individual HPV type was low. HPV16 was the most frequently detected type by PCR (6.1%), serology (23.0%), or both (2.1%). Lifetime number of sexual partners and induced abortions were shown to be directly associated with HPV DNA and/or seroprevalence. HPV prevalence in Ulaanbaatar was higher than that detected by similar HPV testing protocols in other populations in Asia or elsewhere and would suggest an important, yet unquantified, cervical cancer burden. Improving cervical cancer prevention, through screening and HPV vaccination, is an important public health issue for Mongolia. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1731–8)

The hOGG1 Ser326Cys Polymorphism and Lung Cancer Risk: A Meta-analysis

Li, H., Hao, X., Zhang, W., Wei, Q., Chen, K. — 2008-07-15

The potentially functional polymorphism Ser326Cys in the human 8-oxoguanine DNA glycosylase (hOGG1) gene has been implicated in lung cancer risk, but published studies have mixed findings. To summarize published data, we did a comprehensive meta-analysis. Two investigators extracted data independently from 17 case control studies published in the PubMed using the search phrases "hOGG1/OGG1/OGG and polymorphism/genetic variation and lung cancer." The meta-analysis included 6,375 cancer cases and 6,406 control subjects. The results showed that individuals carrying the hOGG1 Cys/Cys genotype did not have significantly increased risk of lung cancer [odds ratios (OR), 1.15; 95% (confidence interval) CI, 0.94-1.41] compared with those with the Ser/Ser genotype; similarly, no significant association with lung cancer risk was found either in the recessive (OR, 1.09; 95% CI, 0.90-1.32 for Cys/Cys versus Ser/Cys+Ser/Ser) or dominant model of the Ser326 allele (OR, 1.06; 95% CI, 0.93-1.21 for Cys/Cys+Ser/Cys versus Ser/Ser). However, significantly increased risks were found among Asian subjects (OR, 1.18; 95% CI, 1.01-1.38 for Cys/Cys+Ser/Cys versus Ser/Ser) in a dominant model. In stratified analyses by control source, compared with the Ser/Ser genotype, lung cancer risk associated with the hOGG1 Cys/Cys genotype was significantly increased in population-based studies (OR, 1.32; 95% CI, 1.04-1.67) but not in hospital-based studies (OR, 1.18; 95% CI, 0.98-1.42); in stratified analyses by the smoking status, however, the increased risk was observed only among nonsmokers in a dominant model (OR, 1.32; 95% CI, 1.04-1.67). The meta-analysis suggested that a careful matching should be considered in future larger genetic association studies including multiple ethnic groups. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1739–45)

A Prospective Study of Bowel Motility and Related Factors on Breast Cancer Risk

Maruti, S. S., Lampe, J. W., Potter, J. D., Ready, A., White, E. — 2008-07-15

Background: Estrogen is an established risk factor for breast cancer. Greater bowel motility has been associated with increased estrogen excretion and lower serum estrogen levels, suggesting that it may influence breast cancer risk. However, only one other epidemiologic study thus far, to our knowledge, has examined the relation between bowel motility and breast cancer risk.

Methods: We prospectively examined whether bowel motility, measured by self-reported frequency of bowel movements, and related factors (constipation, laxative use, water consumption, and dietary fiber intake) were associated with incidence of breast cancer among 28,586 postmenopausal women, ages 50 to 76 years, in the Vitamins and Lifestyle study. Cox proportional hazards models were used to estimate multivariate-adjusted relative risks (RR) and 95% confidence intervals (95% CI). From 2000 to 2005, 507 incident invasive breast cancers among the cohort were identified.

Results: Women with very frequent (≥3/d) bowel movements had a 46% decreased risk compared with 1/d women (RR, 0.54; 95% CI, 0.31-0.92), but the test for linear trend was not significant (P_trend = 0.41). Constipation was nonsignificantly associated with increased risk (RR, 1.30 for ≥1/wk versus <1/y; 95% CI, 0.87-1.95). No statistically significant associations were observed for the other study exposures: 10-year chemical laxative use, 10-year use of fiber laxatives, water consumption, and dietary fiber intake.

Conclusion: This study adds limited support to the hypothesis that increased bowel motility lowers breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1746–50)

Polymorphisms in Genes Involved in Sex Hormone Metabolism, Estrogen Plus Progestin Hormone Therapy Use, and Risk of Postmenopausal Breast Cancer

2008-07-15

Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (≥10 years versus never; odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P_trend = 0.0002). Statistically significant interactions between CYP1A1 Ile⁴⁶²Val (P_interaction = 0.04), CYP1A1 MspI (P_interaction = 0.003), CYP1B1 Val⁴³²Leu (P_interaction = 0.007), CYP1B1 Asn⁴⁵³Ser (P_interaction = 0.04) and PGR Val⁶⁶⁰Leu (P_interaction = 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile⁴⁶²Val, CYP1A1 MspI, CYP1B1 Asn⁴⁵³Ser, and PGR Val⁶⁶⁰Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val⁴³² allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu⁴³². Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1751–9)

GSTM1 and GSTT1 Gene Deletions and the Risk for Nasopharyngeal Carcinoma in Han Chinese

Guo, X., O'Brien, S. J., Zeng, Y., Nelson, G. W., Winkler, C. A. — 2008-07-15

Southern China is a major nasopharyngeal carcinoma–endemic region. Environmental factors and genetic susceptibility contribute to nasopharyngeal carcinoma development in this area. Polymorphic deletions of GSTM1 and GSTT1 genes involved in the detoxification of potentially carcinogenic agents may be a risk factor for nasopharyngeal carcinoma. To investigate the roles of genetic variations of GSTM1 and GSTT1 in nasopharyngeal carcinoma susceptibility in the Chinese population, we conducted a case-control study of 350 nasopharyngeal carcinoma cases and 622 controls. GSTM1 and GSTT1 deletion variants were genotyped by multiplex PCR assays. Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (95% CI). No significant association was observed for either GSTM1- or GSTT1-null genotype independently in the contribution to nasopharyngeal carcinoma risk. To explore possible joint effects of the GSTM1- and GSTT1-null polymorphisms with each other and with other risk factors for nasopharyngeal carcinoma, we examined the association between each combined genotype and the risk for nasopharyngeal carcinoma stratified by gender and EBV replication status. We found that individuals who carried GSTM1/GSTT1–double null genotype had a higher risk for nasopharyngeal carcinoma in the male population (odds ratio, 1.76; 95% confidence interval, 1.04-2.97; P = 0.03); however, this was not significant after correction for multiple comparisons. No statistical difference was found between cases and controls in females and the subpopulation positive for immunoglobulin A antibodies to EBV capsid antigen for combined genotypes. Our results suggest that the GSTM1/GSTT1–double null genotype may be a risk factor for nasopharyngeal carcinoma among males in southern China, but this result warrants confirmation in other studies. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1760–3)

Extensive Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Smokers

2008-07-15

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in both unburned tobacco and cigarette smoke. The sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, referred to as total NNAL, is an established urinary biomarker of human NNK uptake. Metabolic activation of NNK to DNA adducts proceeds via -hydroxylation pathways, and 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid) are the principal end products of these pathways in rodents and primates. The purpose of this study was to determine NNK metabolic activation in smokers, as measured by the sum of keto acid and hydroxy acid, relative to total NNAL. To specifically identify NNK-derived keto acid and hydroxy acid, which are also formed from nicotine, we added [pyridine-D₄]NNK to cigarettes that were originally low in NNK, and measured the deuterium-labeled metabolites in the urine of people who smoked these cigarettes. The total amount of [pyridine-D₄]keto acid plus [pyridine-D₄]hydroxy acid averaged 4.00 ± 2.49 nmol/24 h, whereas the average amount of total [pyridine-D₄]NNAL was 0.511 ± 0.368 nmol/24 h. The results of this study show for the first time that NNK metabolic activation is a quantitatively significant pathway in smokers, accounting for ~86% of total urinary excretion of NNK metabolites. The large interindividual variation in the excreted [pyridine-D₄]keto acid and [pyridine-D₄]hydroxy acid among 20 smokers strongly supports our hypothesis that some smokers activate NNK more extensively than others and that the ratio between biomarkers of metabolic activation and detoxification at a given dose of NNK could be a potential indicator of cancer risk.(Cancer Epidemiol Biomarkers Prev 2008;17(7):1764–73)

Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

2008-07-15

Colorectal cancers arising from serrated polyps are characterized by the CpG island methylator phenotype (CIMP) and somatic mutation (V600E) in the BRAF proto-oncogene. Few epidemiologic studies have investigated risk factors for these tumors. We conducted a cohort study of 41,328 residents of Melbourne, Australia that included 9,939 participants of southern European origin and 31,389 of Anglo-Celtic origin. Colorectal adenocarcinomas were identified from population-based cancer registries. BRAF V600E mutation in tumors was determined using a PCR-based allelic discrimination method. Tumors were classified as CIMP positive when at least three of five markers (RUNX3, CACNA1G, SOCS1, NEUROG1, and IGF2) were methylated according to MethyLight analysis. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression with adjustment for risk factors for colorectal cancer. During follow-up, 718 participants were diagnosed with colorectal cancer. CIMP assays were done for 579 and BRAF V600E mutation testing for 582. After adjustment for other risk factors, when compared with people of Anglo-Celtic origin, those of southern European origin had lower incidence of colorectal cancer that had CIMP (HR, 0.32; 95% CI, 0.16-0.67) or BRAF mutations (HR, 0.30; 95% CI, 0.16-0.58) but similar incidence of colorectal cancer without CIMP (HR, 0.86; 95% CI, 0.70-1.05) or BRAF (HR, 0.90; 95% CI, 0.74-1.11). People of southern European origin had lower risk of colorectal cancers with CIMP and BRAF mutation than people of Anglo-Celtic origin, which may in part be due to genetic factors that are less common in people of southern European origin. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1774–80)

Performance of Amplified DNA in an Illumina GoldenGate BeadArray Assay

2008-07-15

Whole genome amplification (WGA) offers a means to enrich DNA quantities for epidemiologic studies. We used an ovarian cancer study of 1,536 single nucleotide polymorphisms (SNPs) and 2,368 samples to assess performance of multiple displacement amplification (MDA) WGA using an Illumina GoldenGate BeadArray. Initial screening revealed successful genotyping for 93.4% of WGA samples and 99.3% of genomic samples, and 93.2% of SNPs for WGA samples and 96.3% of SNPs for genomic samples. SNP failure was predicted by Illumina-provided designability rank, %GC (P ≤ 0.002), and for WGA only, distance to telomere and Illumina-provided SNP score (P ≤ 0.002). Distance to telomere and %GC were highly correlated; adjustment for %GC removed the association between distance to telomere and SNP failure. Although universally high, per-SNP call rates were related to designability rank, SNP score, %GC, minor allele frequency, distance to telomere (P ≤ 0.01), and, for WGA only, Illumina-provided validation class (P < 0.001). We found excellent concordance generally (>99.0%) among 124 WGA:genomic replicates, 15 WGA replicates, 88 replicate aliquots of the same WGA preparation, and 25 genomic replicates. Where there was discordance, it was across WGA:genomic replicates but limited to only a few samples among other replicates suggesting the introduction of error. Designability rank and SNP score correlated with WGA:genomic concordance (P < 0.001). In summary, use of MDA WGA DNA is feasible; however, caution is warranted regarding SNP selection and analysis. We recommend that biological SNP characteristics, notably distance to telomere and GC content (<50% GC recommended), as well as Illumina-provided metrics be considered in the creation of GoldenGate assays using MDA WGA DNA. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1781–9)

Cervical and Vulvar Cancer Risk in Relation to the Joint Effects of Cigarette Smoking and Genetic Variation in Interleukin 2

2008-07-15

Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1790–9)

Genetic Polymorphisms of CYP2E1 and Risk of Colorectal Adenomas in the Self Defense Forces Health Study

Morita, M., Tabata, S., Tajima, O., Yin, G., Abe, H., Kono, S. — 2008-07-15

CYP2E1 is an enzyme involved in the metabolism of N-nitrosamines and other carcinogenic substances. Functional RsaI and 96-bp insertion polymorphisms in 5'-flanking region have drawn interest in relation to the risk of colorectal cancer. We investigated the relation of these genetic polymorphisms and colorectal adenoma, a well-established precursor lesion of colorectal cancer. Subjects were 455 cases of colorectal adenomas and 1,052 controls of normal colonoscopy among men receiving a preretirement health examination in the Self Defense Forces. Genotypes were determined by either PCR-RFLP or PCR method. Statistical adjustment was made for smoking, alcohol use, body mass index, physical activity, and others. Individuals with RsaI c2 allele showed a decreased risk of proximal colon adenomas; adjusted odds ratios (95% confidence interval) of proximal and distal adenomas for the c1/c2 or c2/c2 genotype versus c1/c1 was 0.61 (0.41-0.88) and 0.95 (0.71-1.27), respectively. CYP2E1 96-bp insertion allele was associated with an increased risk of large (≥ 5 mm) adenomas; adjusted odds ratios (95% confidence interval) of large and small adenomas for having at least one insertion allele were 1.41 (1.03-1.94) and 0.94 (0.71-1.25), respectively. A suggestive effect modification was noted for alcohol consumption on the association between RsaI polymorphism and proximal adenomas (P_interaction = 0.09) as well as on the association between 96-bp insertion and large adenomas (P_interaction = 0.05). These findings indicate that variation in activity and inducibility of CYP2E1 contribute to the development of colorectal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1800–7)

Serum {beta}-Glucuronidase Activity in Response to Fruit and Vegetable Supplementation: A Controlled Feeding Study

2008-07-15

Background: Fruit and vegetable (F&V) intake may lower the risk of some cancers. One hypothesized, but understudied, chemopreventive mechanism is that plant food constituents inhibit β-glucuronidase, an acid hydrolase that deconjugates glucuronides.

Methods: We conducted a crossover feeding trial in 63 healthy women and men ages 20 to 40 years to examine the effect of diet on serum β-glucuronidase activity. Participants were randomized to two 2-week experimental diets with an intervening washout period: a diet high in selected citrus fruit, crucifers, and soy (F&V) and a diet devoid of fruits, vegetables, and soy (basal). Serum β-glucuronidase activity was measured during the preintervention, F&V, and basal periods. Linear mixed models were used to obtain effect estimates and 95% confidence intervals (95% CI).

Results: We observed statistically significantly higher β-glucuronidase activity during the F&V than the basal diet (ratio, F&V versus basal diet, 1.09; 95% CI, 1.05-1.13; P < 0.01). These results were probably due to decreased β-glucuronidase activity during the basal diet (ratio, basal period versus preintervention, 0.93; 95% CI, 0.87-0.98; P = 0.01) rather than increased enzyme activity during the F&V diet (ratio, F&V period versus preintervention, 1.01; 95% CI, 0.96-1.06; P = 0.64). Response to the experimental diet did not differ by sex (P_interaction = 0.30), but there was a suggestion of a short-term diet effect at 8 versus 15 days (P_interaction = 0.06).

Conclusion: This intervention of selected F&V did not lower β-glucuronidase activity. Further investigation is needed regarding what other foods and phytochemicals may influence β-glucuronidase activity and effect modifiers of this relation. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1808–12)

Community-Based Mass Ultrasonographic Screening of Hepatocellular Carcinoma among Thrombocytopenic Adults

2008-07-15

Thrombocytopenia has been reported as a valid surrogate for liver cirrhosis and could be used to identify groups at high risk of hepatocellular carcinoma (HCC) for ultrasonographic (US) screening. We designed this two-stage community-based screening for HCC. In 2004, subjects (ages ≥40 years) were invited to undergo comprehensive health examinations, with 17,551 men (ages 63.0 ± 11.5 years) and 39,151 women (ages 59.9 ± 11.7 years) participating. Subjects with platelet counts <150 x 10⁹/L or -fetoprotein (AFP) >20 ng/mL were enrolled for the second-stage US screening; 3,242 subjects (5.7%; male/female, 1,415/1,827; age 66 ± 10 years) were candidates for US screening and 2,983 (92.2%) responded. Of 137 suspected cases, 124 (90.5%) complied with referral for confirmation and 72 (58.1%) were confirmed to be HCC cases (male/female, 41/31; age 68.1 ± 8.8 years). Screening with AFP, thrombocytopenia, or both could identify 0.64% (n = 364), 5.33% (n = 3,205), and 5.7% (n = 3,242) of the high-risk subjects from the population, estimated to include 50.5%, 54.5%, and 71.3% of all HCC cases. Among confirmed patients, tumor diameters were <3 cm for the 27 (37.5%) patients and 3 to 5 cm for the 23 (31.9%) patients. Only 5 (6.9%) patients' conditions were too advanced to be actively treated. This study enrolled only 5.7% of the participants for US, which cover 64.7% to 71.3% of the HCC cases. Most (93%) of the detected cases were caught early enough to undergo effective treatment modalities. This HCC screening protocol should be feasible, economical, and effective. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1813–21)

Mathematical Modeling of Folate Metabolism: Predicted Effects of Genetic Polymorphisms on Mechanisms and Biomarkers Relevant to Carcinogenesis

2008-07-15

Low-folate status and genetic polymorphisms in folate metabolism have been linked to several cancers. Possible biological mechanisms for this association include effects on purine and thymidine synthesis, DNA methylation, or homocysteine concentrations. The influence of genetic variation in folate metabolism on these putative mechanisms or biomarkers of cancer risk has been largely unexplored. We used a mathematical model that simulates folate metabolism biochemistry to predict (a) the effects of polymorphisms with defined effects on enzyme function (MTHFR and TS) and (b) the effects of potential, as-of-yet-unidentified polymorphisms in a comprehensive set of folate-metabolizing enzymes on biomarkers and mechanisms related to cancer risk. The model suggests that there is substantial robustness in the pathway. Our predictions were consistent with measured effects of known polymorphisms in MTHFR and TS on biomarkers. Polymorphisms that alter enzyme function of FTD, FTS, and MTCH are expected to affect purine synthesis, FTS more so under a low-folate status. In addition, MTCH polymorphisms are predicted to influence thymidine synthesis. Polymorphisms in methyltransferases should affect both methylation rates and thymidylate synthesis. Combinations of polymorphisms in MTHFR, TS, and SHMT are expected to affect nucleotide synthesis in a nonlinear fashion. These investigations provide information on effects of genetic polymorphisms on biomarkers, including those that cannot be measured well, and highlight robustness and sensitivity in this complex biological system with regard to genetic variability. Although the proportional changes in biomarkers of risk with individual polymorphisms are frequently small, they may be quite relevant if present over an individual's lifetime. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1822–31)

IGF-I, IGFBP-3, and IGF-I/IGFBP-3 Ratio: No Association with Incident Colorectal Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

2008-07-15

No Association between Parental or Subject Occupation and Brain Tumor Risk

2008-07-15

No Evidence for Linkage with Melanoma in Italian Melanoma-Prone Families

2008-07-15

Cyclin E Overexpression Relates to Ovarian Cancer Histology but not to Risk Factors

Risch, H. A. — 2008-07-15

Cyclin E Overexpression Relates to Ovarian Cancer Histology but not to Risk Factors

Schildraut, J. M., Moorman, P. G., Calingaert, B., Berchuck, A. — 2008-07-15

Subgroup-Specific Associations in the Face of Overall Null Results: Should We Rush In or Fear to Tread?

Weiss, N. S. — 2008-06-16

Determinants of Incidence and Clearance of High-Risk Human Papillomavirus Infections in Rural Rakai, Uganda

2008-06-16

Background: We used self-administered vaginal swabs to assess the incidence and clearance of carcinogenic human papillomavirus (HPV) infections in rural Rakai, Uganda.

Methods: Women provided self-administered vaginal swab at annual home-based visits. Type-specific carcinogenic HPV incidence and clearance and risk factors were assessed.

Results: Carcinogenic HPV incidence was 17.3 per 100 person-years among HIV-positive women compared with 7.0 per 100 person-years among HIV-negative women (P < 0.001). HPV-51 had the highest incidence followed by HPV-16 (1.8 per 100 and 1.5 per 100 person-years, respectively). In multivariate model, HIV-positive women were twice as likely to have incident infection compared with HIV-negative women. Younger women were at higher risk for incident infection, as were women with higher lifetime and recent sexual partners, and high perception of AIDS. Married women were less likely to have incident infection. Approximately half of all carcinogenic HPV infections cleared over the study follow-up of 3 years. HPV-31, HPV-35, and HPV-16 had the lowest clearance (16.7%, 27.9%, and 38.3%, respectively). In multivariate model, HIV-positive, women over 30 years with higher HPV viral, burden and more lifetime sex partners were less likely to clear infections.

Conclusions: Self-collected vaginal swabs provide accurate HPV exposure assessment for studying HPV exposure and epidemiology and can be an important tool for research in populations unwilling to undergo pelvic exam. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1300–7)

Antibiotic Use and the Risk of Lung Cancer

Zhang, H., Garcia Rodriguez, L. A., Hernandez-Diaz, S. — 2008-06-16

Antibiotic use has been associated with an increased risk of cancer in epidemiologic studies. We evaluated the association between antibiotic use and the risk of primary lung cancer by conducting a prospective case-control study nested in a cohort of subjects who were 40 to 84 years old in 1995 to 2004, with at least 2 years of enrollment in The Health Improvement Network. There were 4,336 cases of primary lung cancer. A random sample of 10,000 controls was frequency matched to the cases for age, sex, and calendar year of diagnosis. Antibiotic exposure was measured by the total number of antibiotic prescriptions and the cumulative number of days on antibiotics since enrollment. We discounted exposure 1 year before the date of cancer diagnosis. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Variables such as smoking, chronic obstructive pulmonary disease, respiratory infections, body mass index, and health care utilization were introduced in the model. Compared with subjects with no prescription of antibiotics before the index date, the crude RR of lung cancer was 2.52 (95% CI, 2.25-2.83) among those who received 10 or more prescriptions. The corresponding RR was 1.31 (95% CI, 1.10-1.57) upon adjustment for confounders. We used directed acyclic graphs to illustrate that the observed higher risk of lung cancer among antibiotic users may be due to the increased frequency of infections in patients with subclinical cancer and to shared causes between cancer and infections. Current evidence is insufficient to support or refute a carcinogenic effect of antibiotics. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1308–15)

Infant Feeding and the Incidence of Endometrial Cancer

2008-06-16

Biological mechanisms could support both an inverse and a direct association between exposure to breast milk in infancy and the risk of cancer. Having been breast-fed has been investigated in relation to the risk of breast and other cancer sites, and conflicting results have been reported. The association between infant feeding and the risk of endometrial cancer has not been explored. From 1976 to 2004, we followed 74,757 cancer-free participants in the Nurses' Health Study who had not undergone hysterectomy. Information on infant feeding was self-reported by study participants. A total of 708 incident cases of endometrial cancer were diagnosed during follow-up. After adjusting for age, family history of endometrial cancer, birth weight, premature birth, and birth order, the incidence of endometrial cancer was not associated with ever having been breast-fed (hazards ratio, 0.94; 95% confidence interval, 0.79-1.11) or duration of having been breast-fed [hazards ratio (95% confidence interval): 1.11 (0.80-1.54), 0.84 (0.62-1.13), 1.02 (0.79-1.31), respectively, for ≤3, 4-8, and ≥9 months of having been breastfed; P for trend = 0.88]. There was no significant effect modification by menopausal status, anthropometric factors (somatotype at age 5 or 10 years, body mass index at age 18 years, or current body mass index), or by other early-life exposures (birth weight, premature birth or exposure to parental smoking in childhood). Additional adjustment for adulthood risk factors of endometrial cancer did not materially change the results. Having been breast-fed was not associated with the incidence of endometrial cancer in this cohort, but statistical power for analyses restricted to premenopausal women was limited. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1316–21)

DNA Repair Capacity and Lung Cancer Risk in Never Smokers

Gorlova, O. Y., Weng, S.-F., Zhang, Y., Amos, C. I., Spitz, M. R., Wei, Q. — 2008-06-16

Besides secondhand smoke exposure, few other risk factors for lung cancer in lifetime never smokers have been identified. We present the estimates of lung cancer risk associated with suboptimal DNA repair capacity (DRC) measured by the host-cell reactivation assay in lifetime never smokers using data from 219 cases and 309 matched controls enrolled in a case-control study. Suboptimal DRC level (below the control median) conferred a significantly increased lung cancer risk in never smokers [odds ratio, 1.92; 95% confidence interval (95% CI), 1.3-2.9; P = 0.0024]. There was a 3.38-fold risk for individuals with DRC below the first quartile (95% CI, 1.8-6.3) compared with individuals with DRC above the third quartile. Secondhand smoke exposure in individuals with DRC below the control median was associated with a 3.81-fold risk of lung cancer (95% CI, 2.3-6.4). A 2.49-fold (95% CI, 1.1-5.6) risk was noted for the joint effects of lung cancer family history in first-degree relatives and suboptimal DRC. Relatives of probands (cases and controls) with lowest DRC (below the first quartile) were significantly more likely to be diagnosed with lung cancer (odds ratio, 2.69; 95% CI, 1.1-6.7) compared with relatives of probands with the most proficient DRC (above the third quartile). Relatives of probands with suboptimal (below the control median) versus proficient DRC also had an earlier age at diagnosis with lung cancer, although the only statistically significant difference was in female relatives (55.4 versus 67.7 years; P = 0.03). (Cancer Epidemiol Biomarkers Prev 2008;17(6):1322–8)

Comparing Genetic Ancestry and Self-Described Race in African Americans Born in the United States and in Africa

2008-06-16

Genetic association studies can be used to identify factors that may contribute to disparities in disease evident across different racial and ethnic populations. However, such studies may not account for potential confounding if study populations are genetically heterogeneous. Racial and ethnic classifications have been used as proxies for genetic relatedness. We investigated genetic admixture and developed a questionnaire to explore variables used in constructing racial identity in two cohorts: 50 African Americans and 40 Nigerians. Genetic ancestry was determined by genotyping 107 ancestry informative markers. Ancestry estimates calculated with maximum likelihood estimation were compared with population stratification detected with principal components analysis. Ancestry was approximately 95% west African, 4% European, and 1% Native American in the Nigerian cohort and 83% west African, 15% European, and 2% Native American in the African American cohort. Therefore, self-identification as African American agreed well with inferred west African ancestry. However, the cohorts differed significantly in mean percentage west African and European ancestries (P < 0.0001) and in the variance for individual ancestry (P ≤ 0.01). Among African Americans, no set of questionnaire items effectively estimated degree of west African ancestry, and self-report of a high degree of African ancestry in a three-generation family tree did not accurately predict degree of African ancestry. Our findings suggest that self-reported race and ancestry can predict ancestral clusters but do not reveal the extent of admixture. Genetic classifications of ancestry may provide a more objective and accurate method of defining homogenous populations for the investigation of specific population-disease associations. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1329–38)