bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Age-Specific Incidence Rate Patterns for Different Histopathologic Types of Breast Carcinoma
Authors: Anderson William F. , Chu Kenneth C. , Chang Shine , Sherman Mark E.
Published: June 2022

Objective: The age-specific incidence rate curve for breast carcinoma overall increases rapidly until age 50 years, and then continues to increase at a slower rate for older women. In this analysis, our objective was to compare age-specific incidence rate patterns for different morphologic types of breast carcinoma. Materials and methods: We analyzed age-specific incidence rate curves by histopathologic subclassification using records from 11 standard National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries, diagnosed during the years 1992 to 1999. Data were examined by age <50 and ≥50 years to simulate menopause. Results: Age-specific incidence rate curves showed three dominant patterns: (1) Rates for infiltrating duct carcinoma of no special type (duct NST), tubular, and lobular carcinomas increased rapidly until age 50 years then rose more slowly. (2) Rates for medullary and inflammatory breast carcinomas increased rapidly until age 50 years then failed to increase. (3) Rates for papillary and mucinous carcinomas increased steadily at all ages. Rate patterns varied by estrogen receptor expression but were unaffected by SEER registry, race, nodal status, or grade. Conclusion: Age-specific incidence rates for breast carcinomas differed by histopathologic type. Rates that failed to increase after 50 years suggested that menopause had greater impact on medullary and inflammatory carcinomas than on duct NST, tubular, and lobular carcinomas. Menopause did not seem to have any effect on papillary or mucinous carcinomas as evidenced by steadily rising rates at all ages. Future etiologic and/or prevention studies should consider the impact of age-specific risk factors and/or exposures on different histopathologic types of breast carcinomas.
Testicular, Other Genital, and Breast Cancers in First-Degree Relatives of Testicular Cancer Patients and Controls
Authors: Bromen Katja , Stang Andreas , Baumgardt-Elms Cornelia , Stegmaier Christa , Ahrens Wolfgang , Metz Klaus A. , Jöckel Karl-Heinz
Published: June 2022

Previous studies showed an increased prevalence of testicular cancer among fathers and brothers of testicular cancer patients. We examined whether testicular, other genital, and breast cancers aggregate in parents and siblings of testicular cancer patients in a population-based case-control study, including males, ages 15 to 69 years at diagnosis, with primary malignant tumors of the testes or extragonadal germ cell tumors. Controls were ascertained through the mandatory registries of residents and frequency matched to the cases by age and region of residence. In a face-to-face interview, 269 cases and 797 controls provided health-related information on parents and siblings. We calculated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) based on the generalized estimating equations technique, adjusting for the matching variables and relatives' age. Three (1.1%) fathers and eight (3.2%) brothers of cases were affected with testicular cancer compared with four (0.5%) fathers and two (0.2%) brothers of controls. The OR (95% CI) of familial testicular cancer was 6.6 (2.35-18.77). Only nonseminoma patients had fathers with testicular cancer, whereas the affected brothers were all related to seminoma patients. Overall, we found an increased risk for genital other than testicular cancers (OR 2.5, 95% CI 1.43-4.43). For breast cancer, we detected an increased risk in sisters (OR 9.5, 95% CI 2.01-45.16, adjusted for age of study participant and age of sister) but not in mothers. Our findings support the hypothesis that testicular and other genital cancers have a common familial component that may be due to genetic and shared exogenous factors such as estrogen exposure during fetal development.
Stability of Measurements of Biomarkers of Oxidative Stress in Blood Over 36 Hours
Authors: Wu Tianying , Rifai Nader , Roberts L. Jackson , Willett Walter C. , Rimm Eric B.
Published: June 2022

Oxidative stress is hypothesized to play an important role in a variety of chronic diseases, but the short-term and long-term stability of measurements of biomarkers related to oxidative stress remains unclear. The objective of this study was to evaluate the stability of measurements of malondialdehyde (MDA), F2-isoprostanes, and fluorescent oxidation products in blood stored on ice within 36 hours until processing. Whole blood samples from six healthy women were processed at 0, 24, and 36 hours after being stored on ice. MDA was measured by the thiobarbituric acid–reactive substances assay with high-pressure liquid chromatography. F2-isoprostanes were measured by gas chromatography/mass spectrometry. The fluorescent oxidation products were measured by spectrofluorometry. Measurements of fluorescent oxidation products were very stable up to 36 hours. Intraclass correlation coefficients (ICC) were >0.95 for each time interval (0 to 24 and 0 to 36 hours). Measurements of MDA were the least stable. The median increased significantly from 0 to 24 hours and from 0 to 36 hours. The ICC for MDA for each time interval (0 to 24 and 0 to 36 hours) was <0.1. Finally, the median of F2-isoprostane measurements at each time point also increased significantly. ICCs were 0.45 for 0 to 24 hours and 0.09 for 0 to 36 hours. We conclude that measurements of fluorescent oxidation products in blood remain stable for up to 36 hours and may be used in large prospective epidemiologic studies of chronic diseases.
A New Single Nucleotide Polymorphism in the Insulin-Like Growth Factor I Regulatory Region Associates with Colorectal Cancer Risk in Singapore Chinese
Authors: Wong Hui-Lee , DeLellis Katherine , Probst-Hensch Nicole , Koh Woon-Puay , Van Den Berg David , Lee Hin-Peng , Yu Mimi C. , Ingles Sue A.
Published: June 2022

Elevated levels of plasma insulin-like growth factor I (IGF-I) are a potential risk factor for several cancers, including colorectal cancer. Physiologic levels of plasma IGF-I vary greatly; this variation may be in part genetically determined. We identified two single nucleotide polymorphisms (SNP) in perfect linkage disequilibrium with each other and in partial linkage disequilibrium with a previously studied cytosine-adenine microsatellite [-969(CA)n]. We investigated one of the SNPs, -533T/C,and the 969(CA)n in relation to the risk of colorectal cancer in a case-control study nested within a cohort of Singapore Chinese (cases/controls = 290:873). The (CA)21 allele, rather than the previously implicated (CA)19 allele, was associated with a reduced risk of colorectal cancer (odds ratio for 21/21 versus all other genotypes, 0.48; 95% confidence interval, 0.28-0.84). For the -533C/T SNP, persons carrying one or more copies of the C allele had a decreased in risk of colorectal cancer compared with noncarriers (odds ratio for CC/CT versus TT, 0.58; 95% confidence interval, 0.41-0.82). This association was specific for colon, as opposed to rectal cancer and was modified by age. We also examined a functional insulin-like growth factor binding protein (IGFBP3) promoter SNP, -202 A/C, previously reported to predict serum IGFBP3 levels. Although we were able to confirm this genotype-phenotype association, the -202A/C IGFBP3 SNP was not significantly associated with colorectal cancer risk. In conclusion, we report a novel SNP in the IGF-I regulatory region that is associated with colorectal cancer risk.
Dietary and Lifestyle Correlates of Plasma Insulin-Like Growth Factor-I (IGF-I) and IGF Binding Protein-3 (IGFBP-3): The Multiethnic Cohort
Authors: DeLellis Katherine , Rinaldi Sabina , Kaaks Rudolph J. , Kolonel Laurence N. , Henderson Brian , Le Marchand Loic
Published: June 2022

High circulating concentration of insulin-like growth factor-I (IGF-I) and low circulating concentration of IGF binding protein-3 (IGFBP-3) have been associated with increased risk for breast, prostate, and colorectal cancers. Building on previous work in the Multiethnic Cohort (MEC) showing significant differences in IGF-I levels across racial/ethnic groups, we investigated which lifestyle and dietary factors are associated with levels of IGF-I and IGFBP-3 in a random sample of 1,000 MEC participants, which included Native Hawaiian, African American, Japanese, Latino, and White men and women. Crude analyses confirmed the existence of differences in protein levels with race/ethnicity, sex, age, and body size. Reproductive, physical activity, smoking, and diet variables had less consistent effects. In multivariate analyses, IGF-I levels were lower and IGFBP-3 were higher in females versus males. IGF-I and IGFBP-3 declined with increasing age in both genders. Women in the highest quartile of body mass index showed depressed IGF-I and IGFBP-3 levels; in men, height was significantly positively associated with both proteins. In women, alcohol was directly associated with IGFBP-3. Both proteins were lowest among female Latinos. IGF-I was highest among female African Americans. In men, IGFBP-3 was lowest among African Americans. Overall, although these factors were statistically significant determinants of IGF-related protein levels, they did not explain much of the variation in these levels. A positive correlation was found between IGF-I levels (ng/mL) and colon cancer incidence rates (per 100,000) within the MEC by race/ethnicity for both sexes but not for either breast or prostate cancer.
Flow Cytometric Detection of Intracellular Th1/Th2 Cytokines Using Whole Blood: Validation of Immunologic Biomarker for Use in Epidemiologic Studies
Authors: Duramad Paurene , McMahon Christopher W. , Hubbard Alan , Eskenazi Brenda , Holland Nina T.
Published: June 2022

Few biological markers of immune function have been thoroughly validated for use in epidemiologic studies that involve delayed sample processing and analysis. Here, we report our validation results for flow cytometric detection of intracellular T-helper 1/T-helper 2 (Th1/Th2) cytokines using 500 μL of whole blood obtained from children and adults. The detection of Th1/Th2 cytokine profiles by flow cytometry is a practical and mechanistically relevant assay because dysregulated cytokine production has been observed in many immune-mediated disorders, including cancer. We evaluated the intraassay and intraindividual and interindividual variability and the effects of a 24- to 72-hour delayed analysis on Th1 and Th2 end points. We compared the distributions of %CD4 lymphocytes, %Th1, and %Th2 in young children (age 1 year, n = 50) and adults (age 25–52 years, n = 16). Subjects sampled monthly for up to 1 year showed minimal variation in CD4, Th1, and Th2 end points. Delayed analysis of samples (up to 24 hours) resulted in no significant differences in the expression of CD4, Th1, and Th2; however, at 48 and 72 hours, all end points differed significantly from baseline (P < 0.01). A random effects model confirmed that interindividual variability was much greater than intraindividual variability for CD4 and Th1. Compared with adults, children had marginally higher %CD4, similar %Th2, but significantly lower %Th1 (P < 0.01). These results show that flow cytometric detection of CD4, Th1, and Th2 markers using whole blood is reproducible and that these biomarkers can be effectively used in human population studies that involve transported samples, delayed processing and analysis, and limited blood volumes.
Plasma Vitamin D Metabolites and Risk of Colorectal Cancer in Women
Authors: Feskanich Diane , Ma Jing , Fuchs Charles S. , Kirkner Gregory J. , Hankinson Susan E. , Hollis Bruce W. , Giovannucci Edward L.
Published: June 2022

Objective: Experimental evidence suggests that 1,25-dihydroxyvitamin D and its precursor, 25-hydroxyvitamin D [25(OH)D], may aid in the prevention of colorectal cancer. We therefore examined risk in relation to plasma concentrations of these vitamin D metabolites. Methods: In a nested case-control study among women in the Nurses' Health Study, we identified 193 colorectal cancer cases, ages 46 to 78 years, diagnosed up to 11 years after blood collection. Two controls were matched per case on year of birth and month of blood draw. Odds ratios (OR) for risk of colorectal cancer were calculated using conditional logistic regression adjusted for body mass index, physical activity, smoking, family history, use of hormone replacement therapy, aspirin use, and dietary intakes. Results: We found a significant inverse linear association between plasma 25(OH)D and risk of colorectal cancer (P = 0.02). Among women in the highest quintile, the OR (95% confidence interval) was 0.53 (0.27–1.04). This inverse association remained strong when limited to women ≥60 years at blood collection (P = 0.006) but was not apparent among the younger women (P = 0.70). Benefit from higher 25(OH)D concentrations was observed for cancers at the distal colon and rectum (P = 0.02) but was not evident for those at the proximal colon (P = 0.81). In contrast to 25(OH)D, we did not observe an association between 1,25-dihydroxyvitamin D and colorectal cancer, although risk was elevated among the women in the highest quintile if they were also in the lower half of the 25(OH)D distribution (OR, 2.52; 95% confidence interval, 1.04–6.11). Conclusion: From these results and supporting evidence from previous studies, we conclude that higher plasma levels of 25(OH)D are associated with a lower risk of colorectal cancer in older women, particularly for cancers at the distal colon and rectum.
Cytochrome P450 1B1 Gene Polymorphisms and Postmenopausal Endometrial Cancer Risk
Authors: Rylander-Rudqvist Tove , Wedrén Sara , Jonasdottir Gudrun , Ahlberg Susanne , Weiderpass Elisabete , Persson Ingemar , Ingelman-Sundberg Magnus
Published: June 2022

Estrogen unopposed by progestins is a key factor in endometrial cancer etiology. Cytochrome P450 1B1 (CYP1B1), responsible for the 4-hydroxylation of estrogen, may be important in endometrial carcinogenesis, either as a regulator of estrogen availability or as a producer of potentially genotoxic estrogen metabolites. We investigated the association of CYP1B1 genotype and endometrial cancer risk in a population-based case-control study of postmenopausal Swedish women. We used the Expectation-Maximization algorithm to estimate the haplotype frequencies in the population and calculated odds ratios and 95% confidence intervals from conditional logistic regression models. In stratified analysis, we investigated the possible effects of CYP1B1 genotype on endometrial cancer risk in subgroups defined primarily by menopausal hormone use and also by body mass index, smoking, use of combined oral contraceptives, and family history. We genotyped 689 cases and 1,549 controls for the CYP1B1 single nucleotide polymorphisms m2, m3, and m4 and estimated the haplotype frequencies among controls to 0.086, 0.291, 0.452, and 0.169 for the CYP1B1*1, CYP1B1*2, CYP1B1*3, and CYP1B1*4 alleles, respectively. We found no evidence for an overall association between CYP1B1 genotype and endometrial cancer risk, nor was there any clear indication of gene-environment interaction.
Etiology of Hormone Receptor–Defined Breast Cancer: A Systematic Review of the Literature
Authors: Althuis Michelle D. , Fergenbaum Jennifer H. , Garcia-Closas Montserrat , Brinton Louise A. , Madigan M. Patricia , Sherman Mark E.
Published: June 2022

Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor–defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor–positive than hormone receptor–negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor–defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.
A Case-Control Study of Risk Factors for Invasive Cervical Cancer among U.S. Women Exposed to Oncogenic Types of Human Papillomavirus
Authors: Shields Tammy S. , Brinton Louise A. , Burk Robert D. , Wang Sophia S. , Weinstein Stephanie J. , Ziegler Regina G. , Studentsov Yevgeniy Y. , McAdams Mary , Schiffman Mark
Published: June 2022

Oncogenic human papillomavirus (HPV) infections, the necessary cause of most cervical cancers, are common and usually clear within 1 to 2 years. Identifying cofactors that lead to cancer among HPV-infected women has depended mainly on case-control studies defining HPV by DNA testing. DNA testing assesses only current infection; thus, concerns about residual confounding remain. To assess cofactors, we used seropositivity to five oncogenic HPV types as a marker of past exposure and confined our analysis to seropositive controls compared with cancer cases. Study subjects had participated in a multicenter U.S. case-control study conducted in the early 1980s. The detailed questionnaire and stored sera for 235 cases of squamous carcinoma and 486 controls motivated the reanalysis. We measured antibodies to HPV types 16, 18, 31, 45, and 52. Independent, significant predictors of seropositivity among controls included numbers of sexual partners, Black race, and oral contraceptive use. Condom use was protective. Among HPV-exposed women, Papanicolaou screening, Black race, and yeast infection were significantly associated with reduced cancer risk. Current smoking was associated with a 2-fold increase in risk; there were independent, significant trends of increased risk with numbers of cigarettes smoked (P for trend = 0.003) and years of smoking (P for trend = 0.01). Other significant predictors of increased risk included low education and income and history of nonspecific genital infection. Unlike recent HPV DNA-based investigations, based on the use of HPV-seropositive controls in this study, oral contraceptive use was unrelated to the risk of cervical cancer and multiparity was only weakly related to risk. It is particularly worth considering further why studies of different designs are inconsistent regarding the effect of oral contraceptive use.
Reproductive Factors and Risk of Glioma in Women
Authors: Huang Kui , Whelan Elizabeth A. , Ruder Avima M. , Ward Elizabeth M. , Deddens James A. , Davis-King Karen E. , Carreón Tania , Waters Martha A. , Butler Mary Ann , Calvert Geoffrey M. , Schulte Paul A. , Zivkovich Zachary , Heineman Ellen F. , Mandel Jack S. , Morton Roscoe F. , Reding Douglas J. , Rosenman Kenneth D. ,   The Brain Cancer Collaborative Study Group
Published: June 2022

Objective: Glioma is the most common primary malignant brain tumor in adults, responsible for 75% of adult primary malignant brain tumors, yet aside from its association with ionizing radiation, its etiology is poorly understood. Sex differences in brain tumor incidence suggest that hormonal factors may play a role in the etiology of these tumors, but few studies have examined this association in detail. The objective of this study was to explore the role of reproductive factors in the etiology of glioma in women. Method: As part of a population-based case-control study, histologically confirmed primary glioma cases (n = 341 women) diagnosed between January 1, 1995 and January 31, 1997 were identified through clinics and hospitals in four Midwest U.S. states. Controls (n = 527 women) were randomly selected from lists of licensed drivers and Health Care Finance Administration enrollees. In-person interviews with subjects (81%) or their proxies (19%) collected reproductive history and other exposure information. Results: Glioma risk increased with older age at menarche (P for trend = 0.009) but only among postmenopausal women. Compared with women who never breast-fed, women who breast-fed >18 months over their lifetime were at increased risk of glioma (odds ratio, 1.8; 95% confidence interval, 1.1-2.9). Women who reported using hormones for symptoms of menopause had a decreased risk of glioma compared with women who never used such hormones (odds ratio, 0.7; 95% confidence interval, 0.5-1.1). Conclusion: These results support the hypothesis that reproductive hormones play a role in the etiology of glioma among women.
Differential Effects of Helicobacter pylori Eradication on Oxidative DNA Damage at the Gastroesophageal Junction and at the Gastric Antrum
Authors: Farinati Fabio , Cardin Romilda , Russo Valentina M. , Busatto Graziella , Franco Monica , Falda Alessandra , Mescoli Claudia , Rugge Massimo
Published: June 2022

Background and Aim: Helicobacter pylori–associated gastritis causes accumulation of reactive oxygen species in the mucosal compartment. This prospective study evaluates DNA oxidative damage in biopsy samples obtained from both the antrum and the gastroesophageal junction (GEJ) before and after H. pylori eradication.

Patients and Methods: Thirty-two consecutive H. pylori–positive patients underwent endoscopy with multiple biopsy sampling (i.e., antrum, incisura angularis, fundus, and cardia at the GEJ). After H. pylori eradication, 32 patients underwent a checkup endoscopy (mean interval, 5.7 months); in a subgroup of 13 subjects, a third endoscopy procedure was also performed (mean interval, 18 months). Additional biopsy samples (two from the antrum and two from the GEJ) were used to assess 8-hydroxydeoxyguanosine (8OHdG) levels using both high-pressure liquid chromatography with electrochemical detector and ELISA.

Results: In the antral compartment, no significant modifications of 8OHdG levels were assessed after H. pylori eradication. Conversely, following eradication, 8OHdG levels significantly increased (high-pressure liquid chromatography with electrochemical detector, P = 0.04; ELISA method, P = 0.05) in biopsy samples taken from the GEJ, and a further increase was documented in the subgroup of patients who underwent a third endoscopy (P = 0.01). The increasing trend was more relevant in patients in whom H. pylori-cagA–positive strains were eradicated and in those affected by hiatal hernia.

Conclusions: The levels of DNA adducts in the antral mucosa are not modified by H. pylori eradication; conversely, H. pylori eradication significantly increases the oxidative adducts at the GEJ. The clinical and biological importance of this situation and whether and how it relates to a higher risk of precancerous lesions is open to debate.
Effects of a 2-Year Randomized Soy Intervention on Sex Hormone Levels in Premenopausal Women
Authors: Maskarinec Gertraud , Franke Adrian A. , Williams Andrew E. , Hebshi Sandra , Oshiro Caryn , Murphy Suzanne , Stanczyk Frank Z.
Published: June 2022

Objective: Several epidemiologic studies have described protective effects of soy consumption against breast cancer. The goal of this trial among premenopausal women was to examine the effect of soy foods on menstrual cycle length and circulating sex hormone levels.

Methods: This 2-year dietary intervention randomized 220 healthy premenopausal women. The intervention group consumed two daily servings of soy foods containing ∼50 mg of isoflavones; the control group maintained their regular diet. Five blood samples (obtained in months 0, 3, 6, 12, and 24) were taken 5 days after ovulation as determined by an ovulation kit. The serum samples were analyzed for estrone, estradiol, sex hormone binding globulin, androstenedione, and progesterone by immunoassay.

Results: At baseline, both groups had similar demographic, anthropometric, and nutritional characteristics. The dropout rates of 15.6% (17 of 109) in the intervention group and 12.6% (14 of 111) in the control group did not differ significantly. According to soy intake logs, 24-hour recalls, and urinary isoflavone excretion, the women closely adhered to the study regimen. Menstrual cycles became slightly shorter in both groups but did not differ by group. Mixed general linear models indicated no significant intervention effect on any of the serum hormones. However, androstenedione and progesterone decreased significantly over time in both groups.

Conclusions: The results of this study suggest that the preventive effects of soy on breast cancer risk in premenopausal women may not be mediated by circulating sex hormone levels. Different mechanisms of actions or effects of exposure earlier in life are alternate hypotheses that require further investigation.
Serum Insulin-Like Growth Factors, Insulin-Like Growth Factor Binding Proteins, and Breast Cancer Risk in Postmenopausal Women
Authors: Grønbæk Henning , Flyvbjerg Allan , Mellemkjær Lene , Tjønneland Anne , Christensen Jane , Toft Sørensen Henrik , Overvad Kim
Published: June 2022

Background: Studies have shown a positive association between serum insulin-like growth factor (IGF)-I and breast cancer risk in premenopausal but not postmenopausal women. IGF-II and estrogen receptor (ER) status has never been investigated. We examined the association between IGF-I, IGF-II, IGF binding protein (IGFBP)-2, IGFBP-3, and IGFBP-3 protease activity and breast cancer risk in postmenopausal women, taking ER status of the breast cancer into consideration.

Methods: We conducted this case-cohort study within a Danish follow-up study based on 24,697 postmenopausal women. We identified 411 cases with breast cancer and a matched control group including 397 cohort members. We estimated breast cancer risk using Cox regression analysis with adjustment for known breast cancer risk factors.

Results: We observed no association for IGF-I but a positive association between levels of IGFBP-3 and breast cancer risk. Per 500 units higher levels of IGFBP-3, an incidence rate ratio [IRR; 95% confidence interval (95% CI)] of 1.14 (1.00-1.30) was estimated. For ER-positive breast cancer, the IRR (95% CI) was 1.18 (1.05-1.33). IGFBP-3 protease activity was not associated with breast cancer risk. Per 275 units higher levels of IGF-II, an IRR (95% CI) of 1.35 (1.10-1.66) was observed for ER-positive tumors, whereas IGFBP-2 was not associated with breast cancer risk. Adjustment for potential confounders did not change the risk estimate. There was no association between IGF-I, IGF-II, IGFBP-2, or IGFBP-3 and risk of ER-negative breast cancer.

Conclusion: Serum IGFBP-3 and IGF-II levels were positively associated with ER-positive breast cancer risk. This may suggest an important relationship among IGFs, IGFBPs, the ER system, and breast cancer development in postmenopausal women.
Body Mass Index and Risk of Leukemia in Older Women
Authors: Ross Julie A. , Parker Emily , Blair Cindy K. , Cerhan James R. , Folsom Aaron R.
Published: June 2022

Overweight [body mass index (BMI) 25.0-29.9 kg/m2] and obesity (BMI ≥30 kg/m2) are risk factors for several malignancies. The Iowa Women's Health Study was examined to determine whether increased BMI was associated with leukemia development. Over 40,000 Iowa women (ages 55-69 years) completed a self-administered lifestyle and health questionnaire in 1986 that included current height and weight. Two hundred women developed leukemia during the period 1986 to 2001 including 74 acute myelogenous leukemia (AML) and 88 chronic lymphocytic leukemia. The risk of AML was increased among women who reported being overweight or obese (relative risk, 1.9; 95% confidence interval, 1.0-3.4; relative risk, 2.4; 95% confidence interval, 1.3-4.5; Ptrend = 0.006) compared with women of normal weight. There was little evidence of a positive association for chronic lymphocytic leukemia (Ptrend = 0.6). Given the prevalence of overweight and obesity in the United States, the population attributable risk of AML due to obesity could approach 30%.
The Relative Risks of a Low-Nitrosamine Smokeless Tobacco Product Compared with Smoking Cigarettes: Estimates of a Panel of Experts
Authors: Levy David T. , Mumford Elizabeth A. , Cummings K. Michael , Gilpin Elizabeth A. , Giovino Gary , Hyland Andrew , Sweanor David , Warner Kenneth E.
Published: June 2022

A nine-membered panel of experts was asked to determine expert opinions of mortality risks associated with use of low-nitrosamine smokeless tobacco (LN-SLT) marketed for oral use. A modified Delphi approach was employed. For total mortality, the estimated median relative risks for individual users of LN-SLT were 9% and 5% of the risk associated with smoking for those ages 35 to 49 and ≥50 years, respectively. Median mortality risks relative to smoking were estimated to be 2% to 3% for lung cancer, 10% for heart disease, and 15% to 30% for oral cancer. Although individual estimates often varied between 0% and 50%, most panel members were confident or very confident of their estimates by the last round of consultation. In comparison with smoking, experts perceive at least a 90% reduction in the relative risk of LN-SLT use. The risks of using LN-SLT products therefore should not be portrayed as comparable with those of smoking cigarettes as has been the practice of some governmental and public health authorities in the past. Importantly, the overall public health impact of LN-SLT will reflect use patterns, its marketing, and governmental regulation of tobacco products.
MTHFR Polymorphisms, Diet, HRT, and Breast Cancer Risk: The Multiethnic Cohort Study
Authors: Le Marchand Loïc , Haiman Christopher A. , Wilkens Lynne R. , Kolonel Laurence N. , Henderson Brian E.
Published: June 2022

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the metabolism of folate, a nutrient which has recently been found to be inversely related to breast cancer in women who drink alcohol. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with a reduced activity of this enzyme, thereby increasing the availability of folate for thymidylate and purine synthesis. We investigated the relationship of these variants with invasive breast cancer in a case-control study of 1,189 cases and 2,414 controls nested within the Multiethnic Cohort Study. The Multiethnic Cohort Study is a large prospective study of men and predominantly postmenopausal women of Japanese, White, African American, Latino, and Native Hawaiian origin, residing in Hawaii and Los Angeles. We found an overall nonsignificant, weak inverse association between breast cancer risk and the 677TT genotype and no association with the 1298C variant. The odds ratio [OR and 95% confidence interval (95% CI)] for the 677CC, 677CT, and 677TT genotypes were 1.00, 0.98 (0.83-1.15), and 0.86 (0.67-1.09), respectively. Those for the 1298AA, 1298AC, and 1298CC genotypes were 1.00, 0.93 (0.79-1.08), and 1.20 (0.88-1.65), respectively. However, the inverse association with the 677TT genotype was stronger (OR, 0.62; 95% CI 0.39-0.98) among women who were on hormone replacement therapy (HRT) at baseline, and the increased breast cancer risk due to HRT was not observed in women with the 677TT genotype. An increased breast cancer risk was suggested for alcohol intake >10 g/d, when compared with nondrinkers, but only among HRT users with the 677CC genotype (OR, 1.51; 95% CI, 0.96-2.37). Folate intake exhibited no modifying effect on the genotype-breast cancer relationship. These findings suggest that the MTHFR 677TT genotype may confer a 40% decreased breast cancer risk in postmenopausal women using HRT. This is consistent with the role of MTHFR in facilitating the flow of folate for thymidylate and purine synthesis and with the increased nucleic acid need resulting from the hyperproliferative effect of HRT on mammary epithelial cells.
Mammographic Density and Estrogen Receptor Status of Breast Cancer
Authors: Ziv Elad , Tice Jeffrey , Smith-Bindman Rebecca , Shepherd John , Cummings Steven , Kerlikowske Karla
Published: June 2022

Background: The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)–positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.

Methods: We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.

Results: Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).

Conclusion: Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.
Molecular Epidemiology of Physical Activity and Cancer
Authors: Rundle Andrew
Published: June 2022

As in other areas of epidemiology, researchers studying physical activity and cancer have begun to include laboratory analyses of biological specimens in their studies. The incorporation of these “biomarkers” into epidemiology has been termed molecular epidemiology and is an approach primarily developed to study chemical carcinogens. Thus far, there has been no discussion in the field on how the established molecular epidemiologic framework might be adapted for research into physical activity, what methodologic needs exist, what the goals of such an approach might be, and what limitations exist. This article relates the literature on molecular epidemiology to the needs of physical activity research and tries to set research priorities for the field as it moves in this new direction. Although this approach will be very useful for investigating the mechanisms through which physical activity exerts effects, there are several challenges for physical activity epidemiologists in adapting molecular epidemiologic approaches. Primarily, there are currently no available biomarkers that might be considered measures of exposure or biologically effective dose. In addition, most available biomarkers of intermediate effects have been tested in training studies at activity levels much higher than those seen in population-based epidemiologic studies. Thus, it is not clear whether these biomarkers are valid at lower activity levels. Furthermore, the nature of the relationship between activity and many available biomarkers depends very much on the context of the activity. Addressing these issues should be a priority if we are to develop a molecular epidemiologic paradigm for studying physical activity.
Population-Based Prevalence and Age Distribution of Human Papillomavirus Among Women in Santiago, Chile
Authors: Ferreccio Catterina , Prado Rodrigo B. , Luzoro Amaranta V. , Ampuero Sandra Ll. , Snijders Peter J.F. , Meijer Chris J.L.M. , Vaccarella Salvatore V. , Jara Alejandro T. , Puschel Klaus I. , Robles Sylvia C. , Herrero Rolando , Franceschi Silvia F. , Ojeda Jose M.
Published: June 2022

More than 18 types of human papillomavirus (HPV) are associated with cervical cancer, the relative importance of the HPV types may vary in different populations.

Objective: To investigate the types of HPV, age distribution, and risk factors for HPV infection in women from Santiago, Chile.

Methods: We interviewed and obtained two cervical specimens from a population-based random sample of 1,038 sexually active women (age range, 15-69 years). Specimens were tested for the presence of HPV DNA using a GP5+/6+ primer-mediated PCR and for cervical cytologic abnormalities by Papanicolaou smears.

Results: 122 women tested positive for HPV DNA, 87 with high risk types (HR), and 35 with low risks (LR) only. Standardized prevalence of HPV DNA was 14.0% [95% confidence interval (95% CI), 11.5-16.4]. HR HPV by age showed a J reverse curve, whereas LR HPV showed a U curve, both statistically significant in comparison with no effect or with a linear effect. We found 34 HPV types (13 HR and 21 LR); HPV 16, 56, 31, 58, 59, 18, and 52 accounted for 75.4% of HR infections. Thirty-four (3.6%) women had cytologic lesions. Main risk factor for HPV and for cytologic abnormalities was number of lifetime sexual partners, odds ratios for ≥3 versus 1 were 2.8 (95% CI, 1.6-5.0) and 3.8 (95% CI, 1.3-11.4), respectively.

Conclusions: LR HPV presented a clear bimodal age pattern; HR HPV presented a J reverse curve. HPV prevalence was similar to that described in most Latin American countries.
PCR Testing of Pooled Longitudinally Collected Cervical Specimens of Women to Increase the Efficiency of Studying Human Papillomavirus Infection
Authors: Castle Philip E. , Schiffman Mark , Herrero Rolando , Hildesheim Allan , Rodriguez Ana-Cecilia , Bratti M. Concepcion , Wacholder Sholom , Kendal Hortense , Breheny Anne M. , Prior Andrew , Pfeiffer Ruth , Burk Robert D.
Published: June 2022

In large active cohort studies of women investigating human papillomavirus (HPV) and cervical neoplasia, many women will be HPV-negative at all time points and testing of all their cervical specimens is an inefficient use of laboratory resources. The aim of this pilot study was to evaluate whether pooling cervical specimens from the same woman might provide a useful pretest of specimens from women unlikely to have high-grade cervical neoplasia or significant HPV exposure. We selected women (n = 187) participating in the Guanacaste Project for whom we already had HPV testing data on all their specimens from multiple visits (median = 8 visits), who were HPV DNA-negative at enrollment and at their 5- to 7-year exit from the cohort, and had no evidence of high-grade cervical neoplasia. Equal aliquots of cervical specimens from these women were pooled to create a proportional pooled specimen. Aliquots of pooled specimens were tested in a masked fashion by MY09/11 L1 consensus primer PCR. Second aliquots of some pooled specimens (n = 83) were included to assess the reliability of pooled testing. Results were compared with the predicted (expected) results based on the obtained test results of the individual specimens collected at interim visits. There was good overall agreement between observed and expected HPV DNA positivity, with a κ of 0.63 [95% confidence interval (95% CI), 0.51-0.75] and a percent agreement of 83.4% (95% CI, 77.3-88.5%) although the HPV DNA positivity in the pooled specimen was less than expected (P = 0.001). The agreement between observed and expected HPV DNA positivity was related to the number of aliquots pooled, suggesting that positivity was related to viral genome concentrations. The κ and percent agreement for intra-batch reliability of testing pooled specimens were 0.68 (95% CI, 0.53-0.84) and 84.3% (95% CI, 74.7-91.4%), respectively. We conclude that pooling specimens and testing by PCR may be useful for discriminating HPV DNA-positive from completely negative specimen sets in women who are likely to have been HPV DNA-negative.>
Period3 Structural Variation: A Circadian Biomarker Associated with Breast Cancer in Young Women
Authors: Zhu Yong , Brown Heather N. , Zhang Yawei , Stevens Richard G. , Zheng Tongzhang
Published: June 2022

Circadian disruption has been indicated as a risk factor for breast cancer in recent epidemiologic studies. A novel finding in circadian biology is that genes responsible for circadian rhythm also regulate many other biological pathways, including cell proliferation, cell cycle regulation, and apoptosis. Therefore, mutations in circadian genes could conceivably result in deregulation of these processes and contribute to tumor development, and be markers for susceptibility to human cancer. In this study, we investigated the association between an exonic length variation in a circadian gene, Period3 (Per3), and breast cancer risk using blood samples collected from a recently completed breast cancer case-control study in Connecticut. There were 389 Caucasian cases and 432 Caucasian controls included in our analysis. We found that the variant Per3 genotype (heterozygous + homozygous 5-repeat alleles) was associated with an increased risk of breast cancer among premenopausal women (odds ratio, 1.7; 95% confidence interval, 1.0-3.0). Our finding suggests that the circadian genes might be a novel panel of potential biomarkers for breast cancer and worth further investigation.
Human Papillomavirus Capsid Antibody Response to Natural Infection and Risk of Subsequent HPV Infection in HIV-Positive and HIV-Negative Women
Authors: Viscidi Raphael P. , Snyder Brad , Cu-Uvin Susan , Hogan Joseph W. , Clayman Barbara , Klein Robert S. , Sobel Jack , Shah Keerti V.
Published: June 2022

The association between seropositivity to virus-like particles (VLP) of human papillomavirus (HPV) types 16, 18, 31, 35, or 45 and subsequent cervical HPV infection was examined in 829 women with HIV and 413 risk-matched HIV-negative women. We found no statistically significant differences between HPV-seropositive and HPV-seronegative women in the risk of a new infection with the homologous HPV type, with the exception of a reduced risk of HPV 45 infections 4.5 years beyond the baseline serology measurement in HIV-positive women [hazard ratio, 0.21; 95% confidence interval (CI), 0.05-0.89]. Among HIV-negative women, HPV seropositivity was not associated with a statistically significant reduced risk of infections with related viruses in the HPV 16, HPV 18, or “other” HPV groups. Among HIV-positive women, HPV seropositivity was associated with a slightly increased risk of infection with group-related viruses, but the differences were only statistically significant for infection with HPV 16 group viruses (hazard ratio, 1.6; 95% CI, 1.1-2.3) in HPV 18-seropositive women and for infections with “other” HPV group viruses in HPV 31-seropositive women (hazard ratio, 1.45; 95% CI, 1.0-2.0). The lack of a protective immune effect from natural infection is most likely due to the low level of antibody elicited by natural HPV infection and/or the potential for reactivation of HPV, especially in HIV-positive women.
The Association between Race and Attitudes about Predictive Genetic Testing
Authors: Peters Nikki , Rose Abigail , Armstrong Katrina
Published: June 2022

Objective: To investigate differences in attitudes about predictive genetic testing for cancer risk between African-American and Caucasian residents of the city of Philadelphia. Methods: Cross-sectional survey of awareness of and attitudes about predictive genetic testing, using an instrument developed through focus groups with the general public, literature review, and expert opinion. Setting: Municipal County Courthouse of Philadelphia. Respondents: Male and female adults waiting to be assigned to jury duty. Results: Of the 430 respondents, 43% (170) were African-American and 45% (181) Caucasian. Awareness of predictive genetic testing was higher among Caucasians (72%) than African-Americans (49%). After adjustment for age, gender, and educational attainment, African-Americans were more likely to report that the government would use genetic tests to label groups as inferior, and less likely to endorse the potential health benefits of testing, including “help my doctor manage my health care,” “help me change my lifestyle,” and “help scientists find cures for diseases.” These associations remained if the sample was restricted to participants who had heard of genetic testing before the survey. Conclusions: In the city of Philadelphia, awareness of and attitudes about predictive genetic testing for cancer risk differ by race, with lower awareness, less belief in the potential benefits of testing, and more concern about racial discrimination from genetic testing among African-Americans than Caucasians. These differences may result in disparities in the uptake of predictive genetic testing in the future.
Demographic and Psychosocial Factors Associated with Perceived Risk for Colorectal Cancer
Authors: Robb Kathryn A. , Miles Anne , Wardle Jane
Published: June 2022

Objective: The objective of this study was to investigate demographic and psychosocial predictors of perceptions of risk for colorectal cancer (CRC) in a population-based sample. Method: The study was a cross-sectional survey of 18,447 men and women aged 55–64 years. A mailed questionnaire assessed perceived comparative risk for CRC along with demographic characteristics (age, gender, ethnicity, marital status, and socioeconomic status), health-related factors (family history, subjective health and bowel symptoms, and health behaviors), and emotional state (anxiety). Results: Being male and older were associated with lower perceived risk. Having a family history of CRC, poorer subjective health, more symptoms, and higher levels of anxiety were all associated with increased perceived risk of CRC. Smokers and nonexercisers perceived their risk as higher. Conclusion: Misperceptions surrounding the effects of age and gender on CRC risk, as well as the genetic link and pathogenesis of CRC, need to be addressed in risk communications.
Molecular Quality of Exfoliated Cervical Cells: Implications for Molecular Epidemiology and Biomarker Discovery
Authors: Habis Angelique H. , Vernon Suzanne D. , Lee Daisy R. , Verma Mukesh , Unger Elizabeth R.
Published: June 2022

The biologic sample collected in molecular epidemiology studies must accurately reflect the disease being studied and have sufficient molecular quality for the intended assays. Noninvasive sampling methods, such as scrapes or brushes, are increasingly used. In this study, we evaluate the impact of sample collection media and extraction methods on the quality and yield of RNA from routine exfoliated cervical cytology. Excess cellular material remaining on the cytologic collection device after preparation of the routine screening Papanicolaou smear was placed in a variety of collection media and extracted using two commercial kits. The collection media had the largest impact on the yield and quality of RNA as evaluated by denaturing agarose gel electrophoresis and image analysis. Two collection media, PAXgene and PreservCyt, yielded RNA from most samples. The RNA showed some degree of degradation as evidenced by the reduced size of the higher molecular weight ribosomal band. However, with a sensitive gold particle-based detection method, reproducible microarray results were obtained using this RNA.