bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective Study of Alcohol Drinking and Renal Cell Cancer Risk in a Cohort of Finnish Male Smokers
Authors: Mahabir Somdat , Leitzmann Michael F. , Virtanen Mikko J. , Virtamo Jarmo , Pietinen Pirjo , Albanes Demetrius , Taylor Philip R.
Published: June 2022

Of the few studies that have examined alcohol consumption in relation to risk of renal cell cancer (RCC), most are case-control studies. The extent to which alcohol affects RRC risk is unclear. We prospectively examined the association between total alcohol intake as well as specific types of alcoholic beverage and RCC in a large cohort of Finnish male smokers. Men from the Alpha-Tocopherol, BetaCarotene (ATBC) Cancer Prevention Study were followed for 12 years and RCC cases were identified. Alcohol consumption was assessed at baseline using a questionnaire previously shown to be both reproducible and valid. Cox proportional hazards modeling was used to adjust simultaneously for known or suspected risk factors for RCC. We ascertained 195 incident cases of RCC. In multivariate analysis, the relative risks and 95% confidence intervals (CI) of RCC according to increasing quartiles of total alcohol intake were 1.0, 0.91 (0.62-1.33), 0.94 (0.64-1.38), and 0.53 (0.34-0.83), respectively (P value for trend = 0.005); for spirit consumption, 1.0, 0.93 (0.63-1.Fspiait39), 0.84 (0.58-1.20), and 0.55 (0.36-0.85) (P for trend = 0.02); and for beer intake, 1.0, 1.22 (0.85-1.76), 0.83 (0.57-1.22), and 0.55 (0.36-0.85) (P for trend = 0.003). Too few people in this cohort drank wine to assess its association with risk of RCC. These data suggest that alcohol consumption is associated with decreased risk of RCC in male smokers. Because most of the risk reductions were seen at the highest quartile of alcohol intake and alcohol is a risk factor for a number of cancers particularly among smokers, these data should be interpreted with caution.
Peroxisome Proliferator-Activated Receptor-γ Suppresses Cyclooxygenase-2 Expression in Human Prostate Cells
Authors: Sabichi Anita L. , Subbarayan Vemparala , Llansa Norma , Lippman Scott M. , Menter David G.
Published: June 2022

Recent studies have found that cyclooxygenase-2 (COX-2) protein expression was low and inducible with cytokines in prostate cancer cells (in the absence of serum) and that, in contrast, COX-2 expression was high in normal prostate epithelial cells (EC). Peroxisome proliferator-activated receptor-γ (PPAR-γ) was expressed at high levels in the prostate cancer cell line PC-3 but not in ECs. In contrast to previous findings by others, PPAR-γ ligands did not induce PPAR-γ expression in EC or PC-3. The present study examined the relationship between PPAR-γ and COX-2 expression patterns in EC and PC-3 in the presence and absence of serum and/or the PPAR-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). We also evaluated the effects that the forced expression of PPAR-γ1 and PPAR-γ2 had on COX-2 in ECs. We found that expression of PPAR-γ and COX-2 protein was inversely correlated in ECs and PC-3. Low COX-2 expression in PC-3 was up-regulated by serum, and 15d-PGJ2 blocked serum-induced COX-2 expression and activity in a dose-dependent manner. 15d-PGJ2 had no effect on COX-2 expression in ECs or PPAR-γ expression in either cell type. However, forced expression of PPAR-γ1 or PPAR-γ2 in ECs suppressed the high level of endogenous COX-2. This effect was not isoform specific and was augmented by 15d-PGJ2. The present study showed that PPAR-γ activation can be an important regulator of COX-2 in prostate cells and may be an important target for prostate cancer chemoprevention.
Benzene Exposure Assessed by Metabolite Excretion in Estonian Oil Shale Mineworkers: Influence of GlutathioneS-Transferase Polymorphisms
Authors: Sørensen Mette , Poole Jason , Autrup Herman , Muzyka Vladimir , Jensen Annie , Loft Steffen , Knudsen Lisbeth E.
Published: June 2022

Measurement of urinary excretion of the benzene metabolites S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) has been proposed for assessing benzene exposure, in workplaces with relatively high benzene concentrations. Excretion of S-PMA and t,t-MA in underground workers at an oil shale mine were compared with the excretion in workers engaged in various production assignments aboveground. In addition, possible modifying effects of genetic polymorphisms in glutathione S-transferases T1 (GSTT1), M1 (GSTM1), and P1 (GSTP1) on the excretion of S-PMA and t,t-MA were investigated. Fifty underground workers and 50 surface workers participated. Blood samples and three urine samples were collected from each worker: (a) a preshift sample collected the morning after a weekend, (b) a postshift sample 1 collected after the first shift, and (c) a postshift sample 2 collected after the last shift of the week. Personal benzene exposure was 114 ± 35 μg/m3 in surface workers (n = 15) and 190 ± 50 μg/m3 in underground workers (n = 15) in measurements made prior to the study. We found t,t-MA excretion to be significantly higher in underground workers after the end of shifts 1 and 2 compared with the corresponding surface workers. The same picture, although not significant, was seen for S-PMA excretion. Excretion of S-PMA and t,t-MA was found to increase significantly during the working week in underground workers but not in those employed on the surface. Both t,t-MA and S-PMA excretion were significantly higher in smokers compared with nonsmokers. Subjects carrying the GSTT1 wild-type excreted higher concentrations of S-PMA than subjects carrying the null genotype, suggesting that it is a key enzyme in the glutathione conjugation that leads to S-PMA. The results support the use of benzene metabolites as biomarkers for assessment of exposure at modest levels and warrant for further investigations of health risks of occupational benzene exposure in shale oil mines.
Lack of Effect of Celecoxib on Prostaglandin E2 Concentrations in Nipple Aspirate Fluid from Women at Increased Risk of Breast Cancer
Authors: Sauter Edward R. , Schlatter Lisa , Hewett John , Koivunen Debra , Flynn John T.
Published: June 2022

Background: Cyclooxygenase enzymes (COX-1, COX-2, and COX-3) convert arachidonic acid to prostaglandins, prostacyclins, thromboxanes, and other hydroxy fatty acids. Among these, prostaglandin E2 (PGE2) has tumor growth-promoting activity. The COX-2 isoform is the primary enzyme involved in PGE2 production in cancerous tissue.

Objective/Hypothesis: We administered the COX-2 inhibitor celecoxib (200 mg b.i.d.) to women at increased breast cancer risk. Our hypothesis was that PGE2 would be secreted in breast nipple aspirate fluid (NAF), that levels in NAF would be higher than in corresponding plasma, and that celecoxib would decrease PGE2 levels in NAF (reflecting a decreased breast tissue eicosanoid production) and plasma.

Specific Aim: To determine if PGE2 concentrations in NAF and plasma decrease after a 2-week course of celecoxib and then return to baseline 2 weeks after stopping the medication (washout).

Study Design: NAF and plasma were collected before celecoxib treatment, 2 weeks after taking celecoxib, and 2 weeks after washout. Each woman served as her own control.

Results: PGE2 concentrations in NAF and plasma were detectable in samples using two measurement techniques. On average, NAF PGE2 levels were 81-fold higher in NAF than in matched plasma. Technically, there were differences in PGE2 concentrations measured in similar fluids depending on the assay technique used (RIA versus chemiluminescence immunoassay). There were no significant decreases in PGE2 concentrations after celecoxib administration.

Conclusions: PGE2 can be measured in NAF. PGE2 levels are concentrated in NAF when compared with matched plasma samples. Celecoxib 200 mg b.i.d. does not appear to significantly decrease PGE2 concentrations in NAF and plasma.
Association of GSTM1, GSTT1, and GSTP1 Gene Polymorphisms with the Risk of Prostate Cancer: A Meta-analysis
Authors: Ntais Christos , Polycarpou Anastasia , Ioannidis John P.A.
Published: June 2022

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.
Poly (AT) Polymorphism in Intron 11 of the XPC DNA Repair Gene Enhances the Risk of Lung Cancer
Authors: Marín M. Soledad , López-Cima M. Felicitas , García-Castro Laura , Pascual Teresa , Marrón Manuel G. , Tardón Adonina
Published: June 2022

Reduced DNA repair capacity due to inherited polymorphisms may increase the susceptibility to smoking-related cancers. In this report, we investigate the relationship between xeroderma pigmentosum complementary group C poly (AT) insertion/deletion polymorphism (XPC-PAT) of the XPC gene and lung cancer risk in a hospital-based case-control study of 359 newly diagnosed lung cancer patients and 375 control subjects matched on age, sex, and catchment area. The XPC genotype was determined by PCR-RFLP, and the results were analyzed using logistic regression, adjusting for relevant covariates. We found that the frequency of the PAT+/+ genotype was higher in the cases (20.6%) than in the controls (14.1%; P = 0.057) and that the PAT+/+ subjects were at significantly increased risk for lung cancer [adjusted odds ratio (OR), 1.60; 95% confidence interval (95% CI), 1.01-2.55]. Stratified analysis revealed that the risk was higher in former smokers (OR, 2.15; 95% CI, 1.07-4.31) and older people (OR, 2.76; 95% CI, 1.02-7.51), although this probably occurs due to 63.4% of cases older than 73 years being ex-smokers. When stratified by histologic type, the variant genotype was associated with statistically significant increased risk for squamous cell carcinoma (OR, 1.93; 95% CI, 1.06-3.51). In conclusion, our findings support the hypothesis that PAT and intron 11 C/A XPC polymorphisms are linked in the Spanish population and may contribute to the risk of developing lung cancer probably due to a higher frequency of deletion of exon 12 and reduced DNA repair capacity of the XPC protein.
BRCA1 and BRCA2 Mutations in a Study of African American Breast Cancer Patients
Authors: Pal Tuya , Permuth-Wey Jenny , Holtje Tricia , Sutphen Rebecca
Published: June 2022

The spectrum of mutations in BRCA1 and BRCA2 among African Americans has not been well characterized because most studies to date have been done in Caucasian families. According to Myriad Genetic Laboratories, Inc., only ∼3% of individuals undergoing BRCA1/BRCA2 testing reported African American ancestry. Data from previous studies show that among African American women a greater proportion of breast cancer cases are diagnosed at age <45 years in comparison with Caucasians. Because breast cancer occurring at a young age is one of the hallmarks of high penetrance genes, the prevalence, spectrum, and effects of BRCA1/BRCA2 mutations may differ substantially between African Americans and Caucasians, and further investigation is warranted.

We conducted a hospital-based study of African American breast cancer patients with early age at diagnosis (≤45 years) or family history of breast or ovarian cancer. We identified four deleterious mutations in BRCA1 or BRCA2 among the 10 families tested, of which two were novel BRCA2 mutations, one was the west African founder mutation (BRCA1 943ins10), and one was a recurrent mutation that may be a candidate for a second African American founder mutation (BRCA1 IVS13+1G>A). Our results support previous data in demonstrating that (a) the spectrum of mutations among African Americans is unique, (b) family history of breast cancer is an important predictor of hereditary cancer susceptibility among African Americans, and (c) empirical data may be useful in estimating mutation risk among African Americans.
Smoking Topography Predicts Abstinence following Treatment with Nicotine Replacement Therapy
Authors: Strasser Andrew A. , Pickworth Wallace B. , Patterson Freda , Lerman Caryn
Published: June 2022

Objective: Smoking topography refers to how a person smokes a cigarette and includes measures of the number of puffs and puff volume, duration, and velocity. This study examined the relationship between smoking topography and abstinence from cigarettes following nicotine replacement therapy. A secondary objective was to determine the relationship of smoking topography to carbon monoxide (CO) exposure.

Method: Participants (n = 113) smoked one of their preferred brands of cigarette through a smoking topography device prior to participating in an open-label trial of transdermal nicotine versus nicotine nasal spray. A subset of participants (n = 50) provided breath CO samples prior to and following smoking the cigarette.

Results: Mean Vmax [odds ratio (OR), 1.12; 95% confidence interval (95% CI), 1.02-1.24; P = 0.02], mean puff volume (OR, 0.95; 95% CI, 0.91-0.98; P = 0.01), mean interpuff interval (OR, 1.06; 95% CI, 1.00-1.11; P = 0.03), and cigarette type (full flavor versus light/ultralight; OR, 0.35; 95% CI, 0.14-0.89; P = 0.03) were significant predictors of abstinence in a model controlling for treatment group and nicotine dependence. Controlling for time since last cigarette and initial CO level, mean puff velocity (β = 0.171; P = 0.01) was the only significant predictor of CO boost.

Conclusion: These results suggest that smoking topography may be useful to predict abstinence after using nicotine replacement therapy and to assess harm from smoking.
Occupational Exposure to Immunologically Active Agents and Risk for Lymphoma
Authors: Kogevinas Manolis , Zock Jan-Paul , Alvaro Tomas , Garcia-Villanueva Mercedes , Domingo-Domenech Eva , Kennedy Susan , Martínez-Maza Otoniel , de Sanjose Silvia
Published: June 2022

Objectives: We evaluated whether occupational exposure to high molecular weight agents that are associated with asthma and that act predominantly through an immunoglobulin E (IgE)–dependent hypersensitivity mechanism is also associated with risk for specific lymphoma types.

Methods: The Spanish lymphoma case-control study includes 519 newly diagnosed cases of lymphoid neoplasms and 554 hospital controls ages 20 to 80 years. Lymphomas were histologically or cytologically confirmed and classified according to the WHO classification. Lifetime occupational exposure to seven high molecular weight agents such as latex was evaluated through an asthma-specific job-exposure matrix and validated by an industrial hygienist. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, sex, hospital, and occupational exposures.

Results: Subjects exposed to high molecular weight agents had an increased risk for Hodgkin's lymphoma (OR, 2.27; 95% CI, 0.93-5.50), particularly nodular sclerosis (OR, 3.22; 95% CI, 1.14-9.09). ORs did not increase with duration of exposure to these agents. Exposure to high molecular weight agents was not associated with risk of other B-cell lymphomas; for most specific subcategories of B-cell lymphoma, ORs were below unity. A slightly increased OR (95% CI) was seen for mycosis fungoides [1.60 (0.53-4.84)], although overall there was no increased risk for T-cell lymphomas.

Conclusions: Exposure to immunologically active agents among clinically immunocompetent subjects was associated with risk for Hodgkin's lymphoma.
Social Ties and Colorectal Cancer Screening among Blacks and Whites in North Carolina
Authors: Kinney Anita Yeomans , Bloor Lindsey E. , Martin Christopher , Sandler Robert S.
Published: June 2022

Few studies have examined the relationship between social networks and colorectal cancer screening in diverse populations. Prior research suggests that the type of social support as well as the amount or frequency of support available from one's social network may be associated with health outcomes. Therefore, the current study examined relationships between both structural (i.e., quantitative aspects of the social network, such as number of ties and frequency of contact with ties) and functional (i.e., functions provided by social network ties, such as offering emotional or instrumental support) aspects of social ties and utilization of colorectal cancer screening tests. Analyses included 697 randomly selected Blacks and Whites ages 51 to 80 years enrolled as controls in the North Carolina Colon Cancer Study. Social tie and screening information was obtained from face-to-face interviews. Forty-seven percent of participants (40% Blacks and 51% Whites) reported use of one of the options for colorectal cancer screening according to the guidelines at that time. Compared with those with the fewest social connections, those who were most socially connected were more likely to report recent use of colorectal cancer screening [odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.7-6.2]. This association was stronger among Blacks (OR, 3.8; 95% CI, 1.3-10.7) than Whites (OR, 2.9; 95% CI, 1.2-6.9; P for interaction = 0.006). There were also positive associations between being a church group (OR, 1.9; 95% CI, 1.4-2.7) and other group member (OR, 1.6; 95% CI, 1.1-2.2) and screening. Neither emotional (e.g., offering reassurance that one is cared for) nor instrumental (e.g., giving material assistance) support was associated with screening behavior. These data suggest that structural rather than functional aspects of social ties may be important in influencing colorectal cancer screening behavior.
Polymorphisms and Circulating Levels in the Insulin-Like Growth Factor System and Risk of Breast Cancer: A Systematic Review
Authors: Fletcher Olivia , Gibson Lorna , Johnson Nichola , Altmann Dan R. , Holly Jeffrey M.P. , Ashworth Alan , Peto Julian , Silva Isabel dos Santos
Published: June 2022

We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5′ to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5′ to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.
Cross-Sectional Associations of Diet and Insulin-Like Growth Factor Levels in 7- to 8-Year-Old Children
Authors: Rogers Imogen S. , Gunnell David , Emmett Pauline M. , Glynn Louise R. , Dunger David B. , Holly Jeff M. ,   and ALSPAC Study Team
Published: June 2022

Background: The insulin-like growth factors (IGF) are polypeptide hormones which are associated with several adult diseases including cancer and coronary heart disease. The dietary determinants of circulating levels of components of the IGF system are of interest, as these may mediate some of the effects of diet on later health. However, few studies have examined the relationship between diet and IGF levels in children.

Objective: To investigate associations between diet and IGF-I and IGFBP-3 levels in 7- to 8-year-old children.

Methods: This study used subjects participating in the Avon Longitudinal Study of Parents and Children. Diet was assessed using a 3-day unweighed food diary. Confounding variables considered were maternal education, housing tenure, birthweight, and body mass index.

Results: Complete information on dietary intakes, IGF levels, and all confounding variables were available for 521 children (287 boys). IGF-I was positively associated with intakes of protein, magnesium, zinc, calcium, potassium, and phosphorus, and IGFBP-3 was positively associated with energy. The IGF-I/IGFBP-3 ratio was positively associated with intakes of protein, zinc, and phosphorus. There was some evidence that the dietary determinants of the IGF system differed between the sexes. None of the foods examined were strongly associated with IGF levels, in particular, there was no association with red meat or vegetable intake.

Conclusion: These data suggest that the IGF axis in children is affected by diet. This may provide a mechanism whereby childhood diet could have a long-term effect on risk of chronic disease.
Evaluation of Breast Cancer Risk Assessment Techniques: A Cost-effectiveness Analysis
Authors: Ozanne Elissa M. , Esserman Laura J.
Published: June 2022

Objective: Assess the effectiveness and cost-effectiveness of using biomarkers and risk assessment tools to stratify women for breast cancer preventive interventions.

Methods: A Markov model was developed to compare risk management strategies for high-risk women considering chemoprevention. Annual screening is compared to the use of chemoprevention for all women and the use of risk assessment technologies to stratify patients for chemoprevention. The biomarker atypia was used to stratify women by risk. Random fine-needle aspiration (rFNA) and ductal lavage (DL) were evaluated and compared as the risk assessment tools used to discover atypia. Sensitivity analyses explore assumptions regarding the prognostic and predictive characteristics of atypia, both the relative breast cancer risk and benefit from chemoprevention women with atypia incur.

Results: Risk assessment strategies using rFNA or DL in combination with chemoprevention are found to be cost-effective (<$50,000 per life year saved) in high-risk groups under most scenarios. Both strategies were more effective and less costly in younger cohorts. Effectiveness of the risk assessment strategies increased when higher risk and increased benefit from chemoprevention were associated with atypia. Within the scenarios tested, rFNA is less costly than DL.

Conclusion: rFNA and DL appear to be cost-effective in high-risk women, assuming women with detected atypia choose tamoxifen. The tools are largely effective for women who are not motivated to take tamoxifen but would be if atypia were found. As biomarker risk assessment tools better predict the risk of breast cancer and or benefit of interventions, their cost-effectiveness increases.
Prevalence of BRCA1 Mutation Carriers among U.S. Non-Hispanic Whites
Authors: Whittemore Alice S. , Gong Gail , John Esther M. , McGuire Valerie , Li Frederick P. , Ostrow Kimberly L. , DiCioccio Richard , Felberg Anna , West Dee W.
Published: June 2022

Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.
A Prospective Study of Perceived Susceptibility to Breast Cancer and Nonadherence to Mammography Screening Guidelines in African American and White Women Ages 40 to 79 Years
Authors: Calvocoressi Lisa , Kasl Stanislav V. , Lee Carol H. , Stolar Marilyn , Claus Elizabeth B. , Jones Beth A.
Published: June 2022

This prospective study examined the influence of perceived susceptibility to breast cancer on nonadherence to recommended mammography screening guidelines. The study population included 1,229 African American and White women ages 40 to 79 years who obtained an index mammography screening examination at one of five urban hospitals in Connecticut between October 1996 and January 1998. Information on perceived susceptibility to breast cancer and on multiple covariates was obtained by telephone interview on average 1.5 months after the index screening. Subsequent adherence to mammography screening guidelines was ascertained by follow-up interview on average 29 months after the index exam. Across race, age, and family breast cancer history, women who believed that their susceptibility was high (i.e., “very likely” to develop breast cancer) were less likely to adhere to screening guidelines than women who believed that their susceptibility was moderate [adjusted odds ratio (OR), 2.83; 95% confidence interval (CI), 1.51-5.30], but the effect was stronger in older women. Women ages 40 to 49 years (but not ages 50-79 years) who believed that their susceptibility was low (i.e., “not likely” or “a little likely” to develop breast cancer) were also less likely to adhere to guidelines than those who reported moderate susceptibility (adjusted OR, 3.07; 95% CI, 1.66-5.68, and adjusted OR, 2.78; 95% CI, 1.63-4.73). In contrast to most previous studies that found a positive linear relationship between perceived susceptibility to breast cancer and mammography screening, these findings suggest a more complex relationship that should be considered when developing interventions to improve adherence to mammography screening guidelines.
Alcohol Exposure and Breast Cancer: Results of the Women's Contraceptive and Reproductive Experiences Study
Authors: McDonald Jill A. , Mandel Michele G. , Marchbanks Polly A. , Folger Suzanne G. , Daling Janet R. , Ursin Giske , Simon Michael S. , Bernstein Leslie , Strom Brian L. , Norman Sandra A. , Malone Kathleen E. , Weiss Linda K. , Burkman Ronald T. , Weber Anita L. , Spirtas Robert
Published: June 2022

Objectives: To explore associated biological outcomes and clarify the role of timing of exposure in the alcohol-breast cancer relationship.

Methods: In a population-based study of 4,575 women ages 35 to 64 years diagnosed with invasive breast cancer between 1994 and 1998 and 4,682 controls, we collected details of lifetime alcohol use and factors that could confound or modify the alcohol-breast cancer relationship. We used conditional logistic regression to compute the odds of breast cancer among drinkers relative to nondrinkers at all ages and at ages 35 to 49 and 50 to 64 years separately.

Results: Recent consumption (at reference age minus two) of ≥7 drinks per week was associated with increased risk [odds ratio (OR), 1.2; 95% CI, 1.01-1.3] and evidence of dose response was observed. Most of the excess was observed among women ages 50-64 years (OR 1.3; 95% CI, 1.1-1.6), although the test for age interaction was not statistically significant. Exposure later in life seemed more important than early exposure. Excess breast cancer associated with recent consumption was restricted to localized disease. When outcome was examined according to tumor hormone receptor status, highest risks were observed for estrogen receptor–positive/progesterone receptor–negative tumors (OR 1.6; 95% CI, 1.2-2.3).

Conclusions: The effect of timing of alcohol exposure on breast cancer risk is complicated and will require additional study focused on this one issue. Further work is needed to explain how alcohol exposure, sex hormones, and tumor receptor status interact.
Body Size and Composition and Risk of Postmenopausal Breast Cancer
Authors: MacInnis Robert J. , English Dallas R. , Gertig Dorota M. , Hopper John L. , Giles Graham G.
Published: June 2022

Background: Studies of postmenopausal breast cancer have reported positive associations with body size and composition but it is uncertain whether these are due to non-adipose, adipose mass, or central adiposity, and whether they are limited to subgroups defined by age or tumor characteristics.

Methods: In a prospective cohort study of women ages 27 to 75, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis, and central adiposity by waist circumference. Among 13,598 women followed on average for 9.1 years, 357 invasive breast cancers were ascertained via the population cancer registry. Data were obtained on estrogen receptor and progesterone receptor status, grade, and stage.

Results: Estimates of body size such as fat-free mass [hazard ratio per 10 kg increase = 1.45, 95% confidence interval (CI) 1.16-1.82], fat mass (hazard ratio per 10 kg increase = 1.18, 95% CI, 1.06-1.31), and waist circumference (hazard ratio per 10 cm increase = 1.13, 95% CI, 1.03-1.24) were associated with breast cancer risk. There was no association with risk before 15 years postmenopause. About 15 years after menopause, risk increased sharply and remained elevated. There was some evidence that this association might be stronger for estrogen receptor-positive and poorly differentiated tumors but no evidence that it differed by stage.

Conclusion: Given that elements of body size and composition are positively associated with breast cancer risk, although not until 15 or more years postmenopause, it is possible that women could reduce risk by maintaining ideal body weight after menopause.
Phytoestrogen Exposure Correlation with Plasma Estradiol in Postmenopausal Women in European Prospective Investigation of Cancer and Nutrition-Norfolk May Involve Diet-Gene Interactions
Authors: Low Yen-Ling , Taylor James I. , Grace Philip B. , Dowsett Mitch , Scollen Serena , Dunning Alison M. , Mulligan Angela A. , Welch Ailsa A. , Luben Robert N. , Khaw Kay-Tee , Day Nick E. , Wareham Nick J. , Bingham Sheila A.
Published: June 2022

Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = −0.199 to −0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = −0.597 to −0.834, P < 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.
Progesterone Receptor Promoter +331A Polymorphism is Associated with a Reduced Risk of Endometrioid and Clear Cell Ovarian Cancers
Authors: Berchuck Andrew , Schildkraut Joellen M. , Wenham Robert M. , Calingaert Brian , Ali Shazia , Henriott Amy , Halabi Susan , Rodriguez Gustavo C. , Gertig Dorota , Purdie David M. , Kelemen Livia , Spurdle Amanda B. , Marks Jeffrey , Chenevix-Trench Georgia
Published: June 2022

Objective: The progestagenic milieu of pregnancy and oral contraceptive use is protective against epithelial ovarian cancer. A functional single nucleotide polymorphism in the promoter of the progesterone receptor (+331A) alters the relative abundance of the A and B isoforms and has been associated with an increased risk of endometrial and breast cancer. In this study, we sought to determine whether this polymorphism affects ovarian cancer risk.

Methods: The +331G/A polymorphism was genotyped in a population-based, case-control study from North Carolina that included 942 Caucasian subjects (438 cases, 504 controls) and in a confirmatory group from Australia (535 cases, 298 controls). Logistic regression analysis was used to calculate age-adjusted odds ratios (OR).

Results: There was a suggestion of a protective effect of the +331A allele (AA or GA) against ovarian cancer in the North Carolina study [OR, 0.72; 95% confidence interval (95% CI), 0.47-1.10]. Examination of genotype frequencies by histologic type revealed that this was due to a decreased risk of endometrioid and clear cell cancers (OR, 0.30; 95% CI, 0.09-0.97). Similarly, in the Australian study, there was a nonsignificant decrease in the risk of ovarian cancer among those with the +331A allele (OR, 0.83; 95% CI, 0.51-1.35) that was strongest in the endometrioid/clear cell group (OR, 0.60; 95% CI, 0.24-1.44). In the combined U.S.-Australian data that included 174 endometrioid/clear cell cases (166 invasive, 8 borderline), the +331A allele was significantly associated with protection against this subset of ovarian cancers (OR, 0.46; 95% CI, 0.23-0.92). Preliminary evidence of a protective effect of the +331A allele against endometriosis was also noted in control subjects (OR, 0.19; 95% CI, 0.03-1.38).

Conclusions: These findings suggest that the +331G/A progesterone receptor promoter polymorphism may modify the molecular epidemiologic pathway that encompasses both the development of endometriosis and its subsequent transformation into endometrioid/clear cell ovarian cancer.
Low-Dose Topical Delivery of All-Trans Retinoic Acid for Cervical Intraepithelial Neoplasia II and III
Authors: Ruffin Mack T. , Bailey Joanne M. , Normolle Daniel P. , Michael Claire W. , Bieniasz Mary E. , Kmak David C. , Unger Elizabeth R. , Brenner Dean E.
Published: June 2022

Objective: The objective of this study was to determine an effective dose for all-trans retinoic acid (atRA) delivered with a cervical cap and sponge for 4 days to women with cervical intraepithelial neoplasia (CIN) II/III.

Methods: Study participants made up of 175 women with biopsy-proven CIN II/III were randomized to four consecutive days of atRA at one of three doses (0.16%, 0.28%, and 0.36%) or placebo. All subjects underwent a repeat colposcopy evaluation and biopsy of the cervix at 12 weeks.

Results: The study participants mean ages were 27.6 years. The racial distribution was 63% Caucasian, 27% African American, and 8% other. Among participants, 93% were human papillomavirus-positive at baseline with 68% positive for high-risk types. The disease response at 12 weeks to atRA or placebo was not significantly different (P = 0.49) among the four dose groups. Participants with CIN II at baseline were more likely to be free of disease at 12 weeks than participants with CIN III at baseline (P = 0.003). There were no reported systemic adverse events related to drug or placebo exposure and only mild local self-reported and clinician-detected toxicities.

Conclusion: Lower concentrations of atRA applied with a cervical cap for 4 days were no more effective than placebo. However, the rate of histologic regression in biopsied CIN II/III patients was high even over a short time interval, and emphasizes the importance of having a placebo arm and an adequate sample size.
Distribution and Prevalence of Human Papillomavirus Genotypes in Routine Pap Smear of 2,470 Korean Women Determined by DNA Chip
Authors: Hwang Hyo-Sung , Park Misun , Lee Sei-Young , Kwon Kyung-Hun , Pang Myung-Geol
Published: June 2022

Purpose: We examined human papillomavirus (HPV) genotype distribution and prevalence from routine Pap smear cases in Korean women using DNA Chip.

Patients and Methods: A total of 2,470 cervical specimens from women attending routine Pap smear cytology screening in local hospitals was subjected to HPV test. HPV detection and genotyping were done using DNA Chip.

Results: HPV DNA was detected in 44.8% of the patients and in 58.7% of the 861 atypical lesions based on the Bethesda system, including 52.6% of 627 atypical squamous cells of undetermined significance (ASCUS), 69.0% of 168 low-grade squamous intraepithelial lesions (LSIL), and 89.4% of 66 high-grade squamous intraepithelial lesions (HSIL) cases. The most frequently found genotypes in all HPV-positive cases were HPV-16, HPV-52, and HPV-58. HPV-16 was the most prevalent type in within normal limits, ASCUS, and HSIL categories, whereas HPV-51 was most frequently found in LSIL. Multiple infection was identified in about 20% of HPV-positive cases and most of them were that by two different types. HPV-16 was present in the majority of multiple infection cases. A significant decrease in the percentage of multiple infection was observed in HSIL cases compared with ASCUS and LSIL.

Conclusions: The distribution of HPV genotypes in Korean women was revealed to have differences to that of other regions, showing higher frequencies of HPV-52, HPV-58, and HPV-51. HSIL cases were mostly infected by sole HPV-16 whereas LSIL that by various HPV types, suggesting a certain type may become dominant over others as the disease progresses.
Testicular Cancer Incidence in Eight Northern European Countries: Secular and Recent Trends
Authors: Richiardi Lorenzo , Bellocco Rino , Adami Hans-Olov , Torrång Anna , Barlow Lotti , Hakulinen Timo , Rahu Mati , Stengrevics Aivars , Storm Hans , Tretli Steinar , Kurtinaitis Juozas , Tyczynski Jerzy E. , Akre Olof
Published: June 2022

Objective: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer.

Method: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach.

Results: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, −0.3%; 95% confidence interval, −1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 105) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates).

Conclusions: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.
Analysis of Phenanthrols in Human Urine by Gas Chromatography-Mass Spectrometry: Potential Use in Carcinogen Metabolite Phenotyping
Authors: Carmella Steven G. , Chen Menglan , Yagi Haruhiko , Jerina Donald M. , Hecht Stephen S.
Published: June 2022

Phenanthrene is the simplest polycyclic aromatic hydrocarbon (PAH) containing a bay region, a feature closely associated with carcinogenicity. We have proposed that measurement of phenanthrene metabolites in human urine could be used to identify interindividual differences in metabolic activation and detoxification of PAH, and that these differences may be related to cancer susceptibility in smokers and other exposed individuals. Previously, we reported a method for quantitation of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT) in human urine. trans, anti-PheT is the ultimate product of the diol epoxide metabolic activation pathway of phenanthrene. In this study, we have extended our carcinogen metabolite phenotyping approach by developing a method for quantitation of phenanthrols in human urine. PAH phenols such as phenanthrols are considered as detoxification products. After treatment of the urine by β-glucuronidase and arylsulfatase, a fraction enriched in phenanthrols was prepared by partitioning and solid phase extraction. The phenanthrols were silylated and analyzed by gas chromatography-positive ion chemical ionization-mass spectrometry with selected ion monitoring. [ring-13C6]3-phenanthrol was used as an internal standard. Accurate and reproducible quantitation of four phenanthrols, 1-phenanthrol (1-HOPhe), 2-HOPhe, 3-HOPhe, and 4-HOPhe, was readily achieved. In smokers, mean levels of 1-HOPhe (0.96 ± 1.2 pmol/mg creatinine) and 3-HOPhe (0.82 ± 0.62 pmol/mg creatinine) were greater than those of 2-HOPhe (0.47 ± 0.29 pmol/mg creatinine), and 4-HOPhe (0.11 ± 0.07 pmol/mg creatinine). There were no significant differences between the levels of any of the phenanthrols in smokers and nonsmokers. Total levels of the quantified phenanthrols were highly correlated with those of 3-HOPhe. Ratios of phenanthrene metabolites representing activation and detoxification were calculated as trans, anti-PheT divided by 3-HOPhe. There was a 7.5-fold spread of ratios in smokers, and a 12.3-fold spread in nonsmokers, suggesting that this may be a useful parameter for distinguishing individual metabolic responses to PAH exposure.
Longitudinal Associations of Age, Anthropometric and Lifestyle Factors with Serum Total Insulin-Like Growth Factor-I and IGF Binding Protein-3 Levels in Black and White Men: the CARDIA Male Hormone Study
Authors: Gapstur Susan M. , Kopp Peter , Chiu Brian C-H. , Gann Peter H. , Colangelo Laura A. , Liu Kiang
Published: June 2022

Although several studies have assessed cross-sectional correlates of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), there are no longitudinal studies of the correlates of long-term changes in these measures. We examined the 8-year longitudinal associations of age, body mass index (BMI), waist circumference, physical activity, number of cigarettes smoked per day, and alcohol intake with serum total IGF-I and IGFBP-3 concentrations in 622 Black and 796 White male participants of the Coronary Artery Risk Development in Young Adults Study who were ages 20 to 34 years at the time of the first IGF measurement. In generalized estimating equation analyses, IGF-I decreased by 5.6 and 5.9 ng/mL per year increase in age for Black and White men, respectively (P< 0.0001), and there was an age-related decline in IGFBP-3 that was stronger in Whites (P < 0.0001) than Blacks (P = 0.21). Average IGF-I (β = −17.51 ng/mL) and IGFBP-3 (β = −355.4 ng/mL) levels across all three exams were lower in Blacks than Whites (P < 0.0001). Increased BMI was associated with decreased IGF-I (P < 0.0002), but was not associated with IGFBP-3. There were no meaningful associations with waist circumference. Increased physical activity was associated with a decrease in IGFBP-3 (P < 0.05), but was not associated with IGF-I. In White men, there were weak inverse associations between the number of cigarettes smoked per day with IGF-I (P=0.15) and with IGFBP-3 (P = 0.19), and in Black men, increased alcohol intake was associated with a decrease in IGF-I (P = 0.011). In conclusion, these results support an age-related decline and Black-White difference in serum IGF-I and IGFBP-3 levels. Importantly, they suggest that IGF-I and/or IGFBP-3 levels could be influenced by changes in BMI, and perhaps by physical activity, alcohol intake, and cigarette smoking.
Polymorphism in the Thymidylate Synthase Promoter Enhancer Region and Risk of Colorectal Adenomas
Authors: Chen Jia , Kyte Charles , Chan Wendy , Wetmur James G. , Fuchs Charles S. , Giovannucci Edward
Published: June 2022

Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.