bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyp17, Urinary Sex Steroid Levels and Breast Cancer Risk in Postmenopausal Women
Authors: Onland-Moret N. Charlotte , van Gils Carla H. , Roest Mark , Grobbee Diederick E. , Peeters Petra H.M.
Published: September 2005

Endogenous sex hormones play an important role in the etiology of breast cancer. Polymorphisms in genes encoding for enzymes involved in steroidogenesis may therefore play a role in breast cancer risk. Cytochrome P450c17α (Cyp17) functions at key branch points in human steroidogenesis. A T→C transition (A1 and A2 allele) in the 5′ untranslated region may be associated with increased expression of Cyp17. Using a case-cohort design, we studied the effects of the A2 allele on endogenous sex hormone levels and breast cancer risk within a large population-based cohort (n = 9,349) in the Netherlands (the DOM-cohort). Cyp17 genotype was determined in 335 incident postmenopausal breast cancer cases, which occurred after follow-up (median time to follow-up, 19 years) of the entire cohort, and in a random sample of 373 women (subcohort). Concentrations of estrone (E1), estradiol (E2), testosterone, 5α-androstane-3α, 17β-diol (3αD), and creatinine were measured in first-morning urine samples. Only among women with body mass index (BMI) < 25 kg/m2 was the A2A2 genotype associated with higher levels of E1, E2, and 3αD compared with a group of women with either the A1A1 or the A1A2 genotype (e.g., geometric means of E1 in ng/mgcreatinine: A2A2, 2.23; A1A1/A1A2, 1.47; P = 0.03). Adjusted breast cancer rate ratios for women with the A1A2 or A2A2 genotype compared with women with the A1A1 genotype were 0.96 (0.68-1.37) and 0.80 (0.47-1.35), respectively. These results did not differ between women with low and high BMI. In conclusion, this paper shows that women with low BMI and the A2A2 genotype had higher endogenous sex steroid levels compared with women with the A1A1 genotype. However, these increased sex steroid levels are not translated into an increased breast cancer risk in these women.
Exploratory Study of Ovarian Intraepithelial Neoplasia
Authors: Brewer Molly A. , Ranger-Moore James , Baruche Amy , Alberts David S. , Greene Mark , Thompson Deborah , Liu Yun , Davis John , Bartels Peter H.
Published: September 2005

Purpose: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer.

Experimental Design: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the subpopulations of nuclei exhibiting these changes.

Results: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant.

Conclusion: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer.
Modifiable Risk Factors Associated with Clearance of Type-Specific Cervical Human Papillomavirus Infections in a Cohort of University Students
Authors: Richardson Harriet , Abrahamowicz Michal , Tellier Pierre-Paul , Kelsall Gail , du Berger Roxane , Ferenczy Alex , Coutlée François , Franco Eduardo L.
Published: September 2005

Background: Previous findings regarding risk factors for human papillomavirus (HPV) persistence, other than viral determinants, identified from prospective cohort studies have been inconsistent in part because study designs have differed with respect to differing HPV detection methods and varying lengths of follow-up time. Therefore, the objectives of this study were to continue the search for epidemiologic risk factors of persistent cervical HPV infections and determine what behaviors differed between those women with transient HPV infections and those women who cannot clear their type-specific HPV infections.

Methods: Female university students (n = 621) in Montreal were followed for 24 months at 6-month intervals. At each visit, a cervical cell specimen was collected. HPV DNA was detected using the MY09/MY11 PCR protocol and 27 HPV genotypes were identified by the line blot assay (Roche Molecular Systems, Inc., Alameda, CA). Proportional hazards regression was used to estimate the crude and adjusted hazard ratios of clearing a type-specific high-risk (n = 222) or low-risk (n = 105) HPV infection over time according to specific baseline and time-dependent covariates.

Results: Daily consumption of vegetables seemed to increase the rate of HPV clearance independent of type. The use of tampons was associated with a reduced rate of high-risk HPV clearance, whereas regular condom use was associated with an increased rate of low-risk HPV clearance only.

Conclusion: Some proactive measures can be taken to increase the rate of HPV clearance, and there may be some differences between the sets of predictors of low-risk and high-risk HPV clearance.
Chromosomal Instability in Peripheral Blood Lymphocytes and Risk of Prostate Cancer
Authors: El-Zein Randa , Gu Yun , Sierra Monica S. , Spitz Margaret R. , Strom Sara S.
Published: September 2005

Prostate cancer is an extremely complex disease, and it is likely that chromosomal instability is involved in the genetic mechanism of tumorigenesis. Several chromosomes have been labeled as “players” in the development of prostate cancer, among them chromosome 1 and X chromosome have been reported to harbor prostate cancer susceptibility loci. However, there is little information regarding the background levels of chromosome instability in these patients. In this pilot study, we examined spontaneous chromosome instability in short-term lymphocyte cultures from 126 study subjects, 61 prostate cancer patients, and 65 healthy controls. We evaluated chromosomal instability using a fluorescence in situ hybridization assay using two probes targeting specific regions on X chromosome and chromosome 1. Our results showed a significantly higher mean level of spontaneous breaks involving the X chromosome in patients compared with controls (mean ± SE, 2.41 ± 0.26 and 0.62 ± 0.08, respectively; P < 0.001). Similarly, chromosome 1 spontaneous breaks were significantly higher among cases compared with controls (mean ± SE, 1.95 ± 0.24 and 1.09 ± 0.16, respectively; P < 0.001). Using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (95% confidence interval) of 15.53 (5.74 - 42.03; P < 0.001) for spontaneous X chromosome breaks and 3.71 (1.60 - 8.63; P < 0.001) for chromosome 1 breaks and risk of development of prostate cancer. In conclusion, our preliminary results show that spontaneous chromosome instability could be a risk factor for prostate cancer.
Ki-67 Expression in Benign Breast Ductal Cells Obtained by Random Periareolar Fine Needle Aspiration
Authors: Khan Qamar J. , Kimler Bruce F. , Clark Julie , Metheny Trina , Zalles Carola M. , Fabian Carol J.
Published: September 2005

Ki-67 expression in ductal cells obtained by random periareolar fine needle aspiration (RPFNA) is currently being used as a response biomarker in phase II breast cancer chemoprevention trials; however, Ki-67 in RPFNA has not been well studied as a risk predictor for cancer, which would support its use as a response indicator. We examined the expression of Ki-67 in RPFNA specimens with hyperplasia ± atypia obtained from 147 women at high risk for development of breast cancer. Median Ki-67 was 1.4% (range 0-24%). Ki-67 was higher in specimens from women <50 versus those ≥50 (median 2% versus 0.6%; P = 0.006) and from premenopausal women versus postmenopausal women (P = 0.037); however, hormone replacement therapy (predominately low-dose estrogen without progestins) had no effect. By univariate analysis, Ki-67 was positively correlated with ductal cell number (P = 0.001) and hyperplasia with atypia (P = 0.007). By multivariable analysis, the proportion of ductal cells expressing Ki-67 was again predicted by cell number, which, in turn, was predicted by cytologic atypia. The association of Ki-67 expression with cytologic atypia, a known risk factor for development of breast cancer, provides preliminary justification for its use as a response biomarker in phase II chemoprevention trials.
Interindividual Variability in Response to Sodium Dichromate–Induced Oxidative DNA Damage: Role of the Ser326Cys Polymorphism in the DNA-Repair Protein of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine DNA Glycosylase 1
Authors: Lee Amanda J. , Hodges Nikolas J. , Chipman James K.
Published: September 2005

Although the genotoxic mechanism(s) of hexavalent chromium (CrVI) carcinogenicity remain to be fully elucidated, intracellular reduction of CrVI and concomitant generation of reactive intermediates including reactive oxygen species and subsequent oxidative damage to DNA is believed to contribute to the process of carcinogenesis. In the current study, substantial interindividual variation (7.19-25.84% and 8.79-34.72% tail DNA as assessed by conventional and FPG-modified comet assay, respectively) in levels of DNA strand breaks after in vitro treatment of WBC with sodium dichromate (100 μmol/L, 1 hour) was shown within a group of healthy adult volunteers (n = 72) as assessed by both comet and formamidopyrimidine glycosylase–modified comet assays. No statistically significant correlation between glutathione S-transferases M1 or T1, NADPH quinone oxidoreductase 1 (codon 187) and X-ray repair cross complementation factor 1 (codon 194) genotypes and individual levels of DNA damage were observed. However, individuals homozygous for the Cys326 8-oxo 7,8-dihydro-2′-deoxyguanosine glycosylase 1 (OGG1) polymorphism had a statistically significant elevation of formamidopyrimidine glycosylase–dependent oxidative DNA damage after treatment with sodium dichromate when compared with either Ser326/Ser326 or Ser326/Cys326 individuals (P = 0.008 and P = 0.003, respectively). In contrast, no effect of OGG1 genotype on background levels of oxidative DNA damage was observed. When individuals were divided on the basis of OGG1 genotype, Cys326/Cys326 individuals had a statistically significant (P < 0.05, one-way ANOVA followed by Tukey test) higher ratio of oxidative DNA damage to plasma antioxidant capacity than either Ser326/Ser326 or Ser326/Cys326 individuals. The results of this study suggest that the Cys326/Cys326 OGG1 genotype may represent a phenotype that is deficient in the repair of 8-oxo-7,8-dihydro-2′-deoxyguanosine, but only under conditions of cellular oxidative stress. We hypothesize that this may be due to oxidation of the Cys326 residue. In conclusion, the homozygous Cys326 genotype may represent a biomarker of individual susceptibility of lung cancer risk in individuals that are occupationally exposed to CrVI.
Association between Mammographic Breast Density and Breast Cancer Tumor Characteristics
Authors: Aiello Erin J. , Buist Diana S.M. , White Emily , Porter Peggy L.
Published: September 2005

Objective: Few studies have examined the association between breast density and breast cancer tumor characteristics. We examined the association between hormonal, proliferative, and histologic tumor characteristics and mammographic breast density in women with breast cancer.

Methods: We conducted a cross-sectional analysis in 546 women diagnosed with invasive breast cancer to evaluate the associations between breast density and tumor size, lymph node status, lymphatic or vascular invasion, histologic grade, nuclear grade, tumor differentiation, mitotic index, tumor necrosis, Ki-67 proliferation, estrogen receptor, progesterone receptor, p53, p27, cyclin E, Bcl-2, and C-erb-B2 invasion. Breast density was classified as fatty (Breast Imaging Reporting and Data System code 1 or 2; n = 373) or dense (Breast Imaging Reporting and Data System code 3 or 4; n = 173) for the cancer-free breast. A single pathologist measured all tumor markers. We examined whether the relationships were modified by interval cancer or screen-detected cancer.

Results: Women with a tumor size >1.0 cm were more likely to have dense breasts compared with women with a tumor size ≤1.0 cm after adjusting for confounders (odds ratio, 2.0; 95% confidence interval, 1.2-3.4 for tumor sizes 1.1-2.0 cm; odds ratio, 2.3; 95% confidence interval, 1.3-4.4 for tumor sizes 2.1-10 cm). Tumor size, lymph node status, and lymphatic or vascular invasion were positively associated with breast density among screen-detected cancers. Histologic grade and mitotic index were negatively associated with breast density in women diagnosed with an interval cancer.

Conclusions: These results suggest that breast density is related to tumor size, lymph node status, and lymphatic or vascular invasion in screen-detected cancers. Additional studies are needed to address whether these associations are due to density masking the detection of some tumors, a biological relationship, or both.
Oral Contraceptive Use and Risk of Early-Onset Breast Cancer in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations
Authors: Milne Roger L. , Knight Julia A. , John Esther M. , Dite Gillian S. , Balbuena Ronald , Ziogas Argyrios , Andrulis Irene L. , West Dee W. , Li Frederick P. , Southey Melissa C. , Giles Graham G. , McCredie Margaret R.E. , Hopper John L. , Whittemore Alice S. ,   for the Breast Cancer Family Registry
Published: September 2005

Background: Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear.

Methods: Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls.

Results: After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001).

Conclusions: There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.
A Simulation Model for Colorectal Cancer Screening: Potential of Stool Tests with Various Performance Characteristics Compared with Screening Colonoscopy
Authors: Haug Ulrike , Brenner Hermann
Published: September 2005

Objective: Many new stool tests intended to detect neoplastic cells or cell products are developed at present for colorectal cancer (CRC) screening. The aim of this study was to simulate a population-based screening setting to assess and compare the potential for early detection and prevention of CRC of screening based on stool tests with different sensitivity and specificity and of screening with colonoscopy as a primary screening tool.

Method: A Markov model was developed aimed to estimate the proportion of CRC cases which are early detected or prevented due to screening as well as the number of equired stool tests and colonoscopies per early detected or prevented CRC case. Model outcomes were calculated for the offer of annual stool testing from age 55 to 74 in combination with colonoscopic follow-up of positive test results and for the offer of screening colonoscopy as a primary screening tool at ages 55 and 65. The long-lasting risk reduction of colonoscopy allowing the removal of precancerous lesions was taken into account quantitatively.

Results: For a variety of stool tests with different performance characteristics, the proportion of CRC cases early detected or prevented was estimated to be higher for stool testing in combination with colonoscopic follow-up of positive test results compared with screening colonoscopy assuming levels of compliance to be expected for the respective screening scheme. Optimizing performance characteristics of stool tests in terms of detecting precancerous lesions, in addition to those in terms of detecting CRC, seemed to be crucial for maximizing effectiveness of CRC screening with stool tests.

Conclusion: Screening based on new stool tests with colonoscopic follow-up of positive test results might offer a high potential for early detection or prevention of CRC.
Thyroid Cancer Susceptibility and THRA1 and BAT-40 Repeats Polymorphisms
Authors: Baida Aida , Farrington Susan M. , Galofré Pere , Marcos Ricard , Velázquez Antonia
Published: September 2005

Although genetic and environmental factors have been identified in the etiology of thyroid cancer, the specific genetic implications in sporadic thyroid tumors are poorly understood but, as in other common cancers, low-penetrance susceptibility genes are believed to be crucial in the tumorigenesis processes. Here, we have carried out a case-control study to investigate whether there is an association between THRA1 CA repeat or BAT-40 A repeat polymorphisms and thyroid cancer risk. The THRA1 repeat resides in the thyroid hormone receptor-α1 gene, which is associated with thyroid cancer and whose expression depends on the THRA1 repeat size. We also analyzed the BAT-40 repeat that maps to chromosome 1, a region known to be involved in thyroid cancer. This repeat is located in the 3-β-hydroxysteroid dehydrogenase gene that is associated with prostate cancer susceptibility. The THRA1 repeat was genotyped in 212 thyroid cancer patients and 141 controls of a Spanish population. From these individuals, 207 patients and 138 controls were also analyzed for the BAT-40 marker. No significant difference in the THRA1 allele distribution between patients and controls was found, although short alleles (<128 bp) might have some protective effect on thyroid cancer risk of carriers (odds ratio, 0.50; 95% confidence interval, 0.22-1.13; P = 0.094). By contrast, the BAT-40 allele distribution in patients was significantly different with respect to control (P = 0.035). Essentially, the difference were found in the genotypes involving the 111- to 115-bp allele range, which seem to be associated with a protective effect on thyroid cancer susceptibility in the studied population (odds ratio, 0.18; 95% confidence interval, 0.01-0.57; P = 0.02). Therefore, our results indicate that the BAT-40 containing region and to a less extend the thyroid hormone receptor-α1 gene are related to thyroid cancer susceptibility. To our knowledge, this is the first study reporting the identification of genetic factors for thyroid cancer susceptibility.
IGF1 (CA)19 Repeat and IGFBP3 -202 A/C Genotypes and the Risk of Prostate Cancer in Black and White Men
Authors: Schildkraut Joellen M. , Demark-Wahnefried Wendy , Wenham Robert M. , Grubber Janet , Jeffreys Amy S. , Grambow Steven C. , Marks Jeffrey R. , Moorman Patricia G. , Hoyo Cathrine , Ali Shazia , Walther Philip J.
Published: September 2005

We investigated the relationship between the insulin-like growth factor-1 (IGF1) cytosine-adenine repeat (CA)19 polymorphism located upstream of the gene's transcription start site, the insulin-like growth factor binding protein-3 (IGFBP3) −202 A/C promoter region polymorphism, and prostate cancer risk in Black and White men. Study subjects were U.S. veterans ages 41 to 75 years identified at the Durham Veterans Administration Medical Center over a 2.5-year period. Controls (n = 93) were frequency matched to cases (n = 100) based on race (Black or White) and age. Multivariable unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the polymorphisms and prostate cancer risk. For Blacks and Whites combined, an inverse association between prostate cancer and being homozygous for the most common IGF1 repeat allele, (CA)19, (adjusted OR, 0.3; 95% CI, 0.1-0.7) was observed. Similar associations were noted for both Blacks (OR, 0.2; 95% CI, 0.0-0.8) and Whites (OR, 0.4; 95% CI, 0.1-1.6) separately. No statistically significant associations between the IGFBP3 C allele and prostate cancer were noted for Blacks (adjusted OR, 2.3; 95% CI, 0.8-6.2) or Whites (OR, 1.0; 95% CI, 0.3-3.1). The prevalence of the homozygous IGF1 (CA)19 genotype was much lower in Black controls (21%) than White controls (46%), which may, in part, explain the increased prostate cancer incidence in Black versus White men. Further research is needed to confirm these findings.
Detection of Alkaline Sphingomyelinase Activity in Human Stool: Proposed Role as a New Diagnostic and Prognostic Marker of Colorectal Cancer
Authors: Di Marzio Luisa , Di Leo Alfredo , Cinque Benedetta , Fanini Donatella , Agnifili Alessio , Berloco Pasquale , Linsalata Michele , Lorusso Dionigi , Barone Michele , De Simone Claudio , Cifone Maria Grazia
Published: September 2005

Objectives: Intestinal alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of messengers able to trigger the rapid turnover and apoptosis in intestinal epithelial cells. Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with human colorectal neoplasms. The aim of this study was to analyze the alkaline sphingomyelinase activity in feces from healthy subjects and colorectal adenocarcinoma patients and to correlate it with the enzyme activity in intestinal tissues.

Materials and Methods: The enzyme activity was measured both in the intestinal samples from 12 healthy controls and 51 patients with colorectal adenocarcinoma (tumoral and paratumoral tissue) and in the fecal samples of 34 healthy subjects and 29 patients with adenocarcinoma. The relation between sphingomyelinase activity and Dukes' stage, cell differentiation degree, age, and gender was also analyzed.

Results: Alkaline sphingomyelinase was significantly decreased (P < 0.001; mean reduction >90%) in tumoral intestinal mucosa of patients compared with controls independently of Dukes' stage and tumor differentiation grade. Interestingly, the enzyme activity in histologically normal paratumoral tissues was statistically lower than control samples (P < 0.001). As occurs in neoplastic tissues, a relevant mean reduction (P < 0.0001; almost 90%) of alkaline sphingomyelinase was revealed in stool samples from tumor patients when compared with controls.

Conclusion: These findings may have implications for cancer biology and perhaps also for the design of clinical test, thus suggesting that the fecal sphingomyelinase activity could really reflect the human intestinal mucosa enzyme level and could represent a new marker for human colorectal adenocarcinoma, mainly taking into account its early appearance in intestinal neoplasms.
Antibody Responses to Simian Virus 40 T Antigen: A Case-Control Study of Non-Hodgkin Lymphoma
Authors: Engels Eric A. , Chen Jinbo , Hartge Patricia , Cerhan James R. , Davis Scott , Severson Richard K. , Cozen Wendy , Viscidi Raphael P.
Published: September 2005

A possible role for SV40, a macaque polyomavirus, in non-Hodgkin lymphoma (NHL) in humans was raised recently by the reported detection of SV40 DNA in tumor tissue. Animals with SV40-induced tumors frequently produce high-level antibodies against T antigen, the SV40 oncoprotein. In this study, we assessed whether SV40 T antibody measured in humans supported a relationship between SV40 and NHL. Subjects were sampled from a U.S. population-based case-control study of NHL, according to presence of antibodies against capsids of SV40 and BK, a related human polyomavirus (n = 85 cases, n = 95 controls). T antibody was measured by enzyme immunoassay. We also evaluated serum specimens from SV40-infected and SV40-uninfected macaques (n = 19 and n = 8, respectively), SV40-uninfected hamsters (n = 5), and hamsters with SV40-induced tumors (n = 10). Hamsters with SV40-induced tumors all produced robust SV40 T antibody [median absorbance, 0.99), whereas SV40-uninfected hamsters and macaques had much lower levels (median absorbance, 0.05 and 0.04, respectively). NHL cases, controls, and SV40-infected macaques resembled these latter two groups, generally showing only low-level T antibody (median absorbance, 0.03, 0.04, and 0.04, respectively). Overall, only five cases (6%) and five controls (5%) had T antibody responses classified as seropositive (odds ratio, 1.2; 95% confidence interval, 0.3-4.6). Interestingly, all 10 humans with T antibody responses also showed antibody responses to BK capsid. We found no association between the presence of T antibody and NHL, arguing against SV40 as a cause of NHL. Infrequent and low-level T antibody responses among humans could represent cross-reactivity to BK virus T antigen.
DNA Damage from Polycyclic Aromatic Hydrocarbons Measured by Benzo[a]pyrene-DNA Adducts in Mothers and Newborns from Northern Manhattan, The World Trade Center Area, Poland, and China
Authors: Perera Frederica , Tang Deliang , Whyatt Robin , Lederman Sally Ann , Jedrychowski Wieslaw
Published: September 2005

Polycyclic aromatic hydrocarbons (PAH), of which benzo[a]pyrene is a representative member, are combustion-related environmental pollutants and include known carcinogens. Laboratory animal studies indicate that the dose of PAHs to the fetus is on the order of a 10th that to the mother and that there is heightened susceptibility to PAH-induced carcinogenesis during the fetal and infancy periods. Carcinogen-DNA adducts, a measure of procarcinogenic genetic damage, are considered a biomarker of increased cancer risk. Here we compare the levels of benzo[a]pyrene-DNA adducts as a proxy for PAH-DNA damage measured in maternal blood and newborn cord blood obtained at delivery in four different populations of mothers (total of 867) and newborns (total of 822), representing a 30-fold range of exposure to ambient PAHs. The populations include residents in Northern Manhattan, participants in a study of the effects of the World Trade Center disaster, residents in Krakow, Poland, and residents in Tongliang, China. Mean adduct concentrations in both maternal and cord blood and the proportion of samples with detectable adducts, increased across the populations [Northern Manhattan < World Trade Center (WTC) < Krakow < Tongliang], consistent with the trend in estimated ambient exposure to PAHs (P < 0.001). For mothers, the means in the respective populations were Northern Manhattan (0.21 adducts per 108 nucleotides), WTC (0.23 adducts per 108 nucleotides), Krakow (0.28 adducts per 108 nucleotides), Tongliang (0.31 adducts per 108 nucleotides); the corresponding means in the newborns were Northern Manhattan (0.23), WTC (0.24), Krakow (0.29), Tongliang (0.31). The percentage of mothers with detectable levels of adducts in the respective populations were Northern Manhattan (36.8%), WTC (57.5%), Krakow (72.9%), Tongliang (73.4%); the corresponding percentages among the newborns were Northern Manhattan (42.4%), WTC (60.6%), Krakow (71.1%), Tongliang (79.5%). Despite the estimated 10-fold lower PAH dose to the fetus based on laboratory animal experiments, the adduct levels in the newborns were similar to or higher than in the mothers. This study suggests that the fetus may be 10-fold more susceptible to DNA damage than the mother and that in utero exposure to polycyclic aromatic hydrocarbons may disproportionately increase carcinogenic risk. The data support preventive policies to limit PAH exposure to pregnant women and children.
Does Health Insurance Coverage of Office Visits Influence Colorectal Cancer Testing?
Authors: Varghese Reuben K. , Friedman Carol , Ahmed Faruque , Franks Adele L. , Manning Marsha , Seeff Laura C.
Published: September 2005

Objective: To assess the effect of differing health insurance coverage of physician office visits on the use of colorectal cancer (CRC) tests among an employed and insured population.

Method: Cohort study of persons ages 50 to 64 years enrolled in fee-for-service (FFS) or preferred provider organization (PPO) health plans, where FFS plan enrollees bear disproportionate share of office visit coverage, for the period 1995 through 1999.

Results: Compared with FFS plans, enrollees in PPO plans were significantly more likely to obtain CRC tests [adjusted relative risk (RRa), 1.27; 95% confidence intervals (CI), 1.21-1.24]. The association was more pronounced among hourly individuals (RRa, 1.43; 95% CI, 1.41-1.45) than among salaried individuals (RRa, 1.09; 95% CI, 1.05-1.10), consistent with a greater differential in office visit coverage among the hourly group.

Conclusions: Disproportionate cost-sharing seems to have a negative effect on the use of CRC tests most likely by discouraging nonacute care physician office visits.
Genetic Factors in Catechol Estrogen Metabolism in Relation to the Risk of Endometrial Cancer
Authors: Doherty Jennifer A. , Weiss Noel S. , Freeman Robert J. , Dightman Douglas A. , Thornton Perry J. , Houck John R. , Voigt Lynda F. , Rossing Mary Anne , Schwartz Stephen M. , Chen Chu
Published: September 2005

2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a population-based case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile462Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr461Asn, CYP1A2 A734C, and CYP1B1 Leu432Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.
Increased Retinoic Acid Receptor-β4 Correlates In vivo with Reduced Retinoic Acid Receptor-β2 in Esophageal Squamous Cell Carcinoma
Authors: Xu Xiao-chun , Lee J. Jack , Wu Tsung-Teh , Hoque Ashraful , Ajani Jeffer A. , Lippman Scott M.
Published: September 2005

Different retinoic acid receptor-β (RAR-β) isoforms seem to have contrasting biological effects in human carcinogenesis. Both in vitro and in vivo data indicate that RAR-β2 expression is frequently lost or reduced (and transfecting RAR-β2 suppresses growth and promotes apoptosis) in various cancer cells and tissues, whereas RAR-β4 expression is increased in several cancer cell lines. To clarify the effects of different RAR-β isoforms in esophageal carcinogenesis, we used real-time quantitative reverse transcription-PCR to assess in vivo RAR-β mRNA levels in specimens of normal and malignant human esophageal tissue, comparing these levels with each other and the expressions of other genes. RAR-β2 mRNA expression was significantly reduced (i.e., lower in cancer than normal tissue) in 67% (18 of 27, P = 0.001) and RAR-β4 mRNA was increased in 52% (14 of 27, P = 0.054) of our esophageal cancer cases. The expressions of RAR-β1, chicken ovalbumin upstream promoter-transcription factor-I (COUP-TFI), COUP-TFII, and peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA were reduced, whereas epidermal growth factor receptor and cyclin D1 expressions were increased in tumor compared with in normal tissues. Reduced RAR-β2 expression correlated with increased RAR-β4 expression (P = 0.002) and with the suppression of COUP-TFI and COUP-TFII (P = 0.050 and 0.023, respectively) in tumor samples. These are the first in vivo expression patterns of RAR-β2 and RAR-β4 reported in humans or animals and support the in vitro data on these isoforms and their contrasting biological effects in human carcinogenesis.
A DNA Pooling Strategy for Family-Based Association Studies
Authors: Lee Wen-Chung
Published: September 2005

Genome-wide association scans for disease susceptibility genes of complex diseases require genotyping on a massive scale. A DNA pooling strategy for family-based association studies is described, which is robust to population stratification biases and to errors in pooling. It can achieve a statistical efficiency of 0.95 with ∼1 of 8 or fewer genotyping efforts, and an efficiency of 0.90 with ∼1 of 16 or fewer efforts compared with individual genotyping. The pooling method described in this article provides a tradeoff between genotyping efforts and subject recruitment efforts.
Dietary Intake of Heterocyclic Amines and Benzo(a)Pyrene: Associations with Pancreatic Cancer
Authors: Anderson Kristin E. , Kadlubar Fred F. , Kulldorff Martin , Harnack Lisa , Gross Myron , Lang Nicholas P. , Barber Cheryl , Rothman Nat , Sinha Rashmi
Published: September 2005

Objective: Heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons, formed in temperature- and time-dependent manners during the cooking of meat, are mutagens and carcinogens. We sought to assess the association between dietary intake of HCA and benzo(a)pyrene [B(a)P] and exocrine pancreatic cancer in a population-based case-control study.

Methods: Subjects (193 cases and 674 controls) provided information on their usual meat intake and preparation method, e.g., stewed, fried, or grilled/barbecued, etc. Meat doneness preferences were measured using photographs that showed internal doneness and external brownness. We used a meat-derived HCA, B(a)P, and mutagen database with a questionnaire to estimate intake of PhIP, DiMeIQx, MeIQx, B(a)P, and mutagenic activity (revertants/g of daily meat intake). Data were analyzed with unconditional logistic regression.

Results: In analyses adjusted for age, sex, smoking, education, race, and diabetes, the odds ratio and 95% confidence interval for the highest compared with the lowest quintile were as follows: PhIP, 1.8 (1.0-3.1); DiMeIQx, 2.0 (1.2-3.5); MeIQx, 1.5 (0.9-2.7); B(a)P, 2.2 (1.2-4.0); and mutagenic activity, 2.4 (1.3-4.3).

Conclusions: HCAs and B(a)P from well-done barbecued and pan-fried meats may be associated with increased risk for pancreatic cancer.
Body Mass Index in Relation to Ovarian Cancer Survival
Authors: Zhang Min , Xie Xing , Lee Andy H. , Binns Colin W. , Holman C. D'Arcy J.
Published: September 2005

Evidence for an association between indicators of adiposity and survival after ovarian cancer has been inconsistent. A prospective cohort study was conducted in China to examine the relationship between ovarian cancer survival and body mass index (BMI). From the 214 patients recruited in 1999 to 2000 with histopathologically confirmed invasive epithelial ovarian cancer, 207 patients or their close relatives (96.7% of cases) were traced and followed to 2003. Deaths were recorded and Cox proportional hazards regression was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI) from multivariate models. Reduced survival was observed among patients with BMI ≥ 25 kg/m2 at 5 years before diagnosis (P = 0.001). There were 98 (59.8%) of 164 patients with BMI <25 kg/m2 survived to the time of interview compared with only 15 women (34.9%) among the 43 patients whose BMI was ≥25 kg/m2. The HRs significantly increased with higher BMI at 5 years before diagnosis but not at diagnosis nor at age 21 years. The adjusted HR was 2.33 (95% CI, 1.12-4.87) for BMI of ≥25 versus <20 kg/m2, with a significant dose-response relationship. The HR was 3.31 (95% CI, 1.26-8.73) among patients who had been overweight or obese at age 21 years, but a linear dose-response was not found. We conclude that premorbid BMI may have independent prognostic significance in ovarian cancer.
The Effect of a School-Based Sun Protection Intervention on the Development of Melanocytic Nevi in Children: 6-Year Follow-up
Authors: English Dallas R. , Milne Elizabeth , Jacoby Peter , Giles-Corti Billie , Cross Donna , Johnston Robyn
Published: September 2005

Because nevi share risk factors with melanoma and are strong risk factors for melanoma, they are suitable biomarkers for evaluating sun protection programs. Kidskin was a trial of a school-based sun protection program in Western Australia that included high and moderate intervention groups and a control group. Schools were assigned nonrandomly to groups. The primary outcome was number of nevi on the back. Nevi were counted at baseline, after 4 years intervention and again 2 years later. Linear growth models, allowing for correlated data within schools and children were fitted to the data. The primary analysis included 639 control children, 414 in the moderate and 355 in the high intervention group. Compared with the control group, the relative increase in number of nevi on the back was 0.89 (95% confidence interval, 0.81-0.99) for the high intervention group and 0.94 (95% confidence interval, 0.86-1.04) for the moderate group (P = 0.09). In subgroup analyses of nevi on the back, the association was stronger in boys (P < 0.001) than in girls (P = 0.7), although the test for interaction was not significant (P = 0.11). For the chest, examined in boys, the associations were similar to that for nevi on the back in boys. Associations were weak for nevi on the face and arms (P = 0.2); for this site, there was weak evidence of heterogeneity by sex. Overall, there was weak evidence that the Kidskin intervention reduced the number of new nevi over a 6-year period, but there was stronger evidence of an effect on the trunk in boys.
CYP3A43 Pro340Ala Polymorphism and Prostate Cancer Risk in African Americans and Caucasians
Authors: Stone Angie , Ratnasinghe Luke D. , Emerson Ginny L. , Modali Rama , Lehman Terri , Runnells Gail , Carroll Alindria , Carter Weleetka , Barnhart Samuel , Rasheed Al A. , Greene Graham , Johnson Don E. , Ambrosone Christine B. , Kadlubar Fred F. , Lang Nicholas P.
Published: September 2005

The human cytochrome P450 3A subfamily of enzymes is involved in the metabolism of steroid hormones, carcinogens, and many drugs. A cytosine-to-guanine polymorphism in CYP3A43 results in a proline-to-alanine substitution at codon 340. Although the functional significance of this polymorphism is unknown, we postulate that the substitution of proline, an α-imino acid, with alanine, an amino acid, could be of biochemical significance. In a case-control study with 490 incident prostate cancer cases (124 African Americans and 358 Caucasians) and 494 controls (167 African Americans and 319 Caucasians), we examined the association between CYP3A43 Pro340Ala polymorphism and prostate cancer risk. When all subjects were considered, there was a 3-fold increase in risk of prostate cancer among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 3.0; 95% confidence interval, 1.2-7.2) compared with those with the CYP3A43-Pro/Pro genotype after adjusting for age, race, and smoking. The prevalence of the polymorphism was significantly higher in African Americans than Caucasians (45% versus 13%). In African Americans, there was a 2.6-fold increase in prostate cancer risk among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 2.6; 95% confidence interval, 1.0-7.0) compared with those with the CYP3A43-Pro/Pro genotype. Among Caucasians, the small number of homozygotes precluded computing risk estimates; there were only three individuals with the CYP3A43-Ala/Ala genotype. Our results suggest that the CYP3A43-Pro340Ala polymorphism contributes to prostate cancer risk.
Trends in Cervical Squamous Cell Carcinoma Incidence in 13 European Countries: Changing Risk and the Effects of Screening
Authors: Bray Freddie , Loos Anja H. , McCarron Peter , Weiderpass Elizabete , Arbyn Mark , Møller Henrik , Hakama Matti , Parkin D. Max
Published: September 2005

Despite there being sufficient evidence for the effectiveness of screening by cytology in preventing cancer of the cervix uteri, screening policies vary widely among European countries, and incidence is increasing in younger women. This study analyzes trends in squamous cell carcinoma (SCC) of the cervix uteri in 13 European countries to evaluate effectiveness of screening against a background of changing risk. Age-period-cohort models were fitted and period and cohort effects were estimated; these were considered as primarily indicative of screening interventions and changing etiology, respectively. A unique set of estimates was derived by fixing age slopes to one of several plausible age curves under the assumption that the relation between age and cervical cancer incidence is biologically determined. There were period-specific declines in cervical SCC in several countries, with the largest decreases seen in northern Europe. A pattern emerged across Europe of escalating risk in successive generations born after 1930. In the western European countries, a decrease followed by a stabilization of risk by cohort was accompanied by period-specific declines. In southern Europe, stable period, but increasing cohort trends, were observed. Substantial changes have occurred in cervical SCC incidence in Europe and well-organized screening programs have been highly effective in reducing the incidence of cervical SCC. Screening and changing sexual mores largely explain the changing period- and cohort-specific patterns, respectively. The increasing risk in recent cohorts is of obvious concern particularly in countries where no screening programs are in place. Further investigation of the effectiveness of opportunistic screening is warranted as is the observation of differing risk patterns in young cohorts in countries with relatively similar societal structures.
Obesity, Recreational Physical Activity, and Risk of Pancreatic Cancer In a Large U.S. Cohort
Authors: Patel Alpa V. , Rodriguez Carmen , Bernstein Leslie , Chao Ann , Thun Michael J. , Calle Eugenia E.
Published: September 2005

Background: Obesity and physical activity, in part through their effects on insulin sensitivity, may be modifiable risk factors for pancreatic cancer.

Methods: The authors analyzed data from the American Cancer Society Cancer Prevention Study II Nutrition Cohort to examine the association between measures of adiposity, recreational physical activity, and pancreatic cancer risk. Information on current weight and weight at age 18, location of weight gain, and recreational physical activity were obtained at baseline in 1992 via a self-administered questionnaire for 145,627 men and women who were cancer-free at enrollment. During the 7 years of follow-up, 242 incident pancreatic cancer cases were identified among these participants. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) and to adjust for potential confounding factors including personal history of diabetes and smoking.

Results: We observed an increased risk of pancreatic cancer among obese [body mass index (BMI) ≥ 30] men and women compared with men and women of normal BMI [<25; RR, 2.08; 95% confidence interval (95% CI), 1.48-2.93, Ptrend = 0.0001]. After adjustment for between BMI, risk of pancreatic cancer was independently increased among men and women who reported a tendency for central weight gain compared with men and women reporting a tendency for peripheral weight gain (RR, 1.45; 95% CI, 1.02-2.07). We observed no difference in pancreatic cancer incidence rates between men and women who were most active (>31.5 metabolic equivalent hours per week) at baseline compared with men and women who reported no recreational physical activity (RR, 1.20; 95% CI, 0.63-2.27).

Conclusion: This study, along with several recent studies, supports the hypothesis that obesity and central adiposity are associated with pancreatic cancer risk.
Analyzing Patterns of Staining in Immunohistochemical Studies: Application to a Study of Prostate Cancer Recurrence
Authors: Etzioni Ruth , Hawley Sarah , Billheimer Dean , True Lawrence D. , Knudsen Beatrice
Published: September 2005

Background: Immunohistochemical studies use antibodies to stain tissues with the goal of quantifying protein expression. However, protein expression is often heterogeneous resulting in variable degrees and patterns of staining. This problem is particularly acute in prostate cancer, where tumors are infiltrative and heterogeneous in nature. In this article, we introduce analytic approaches that explicitly consider both the frequency and intensity of tissue staining.

Methods: Compositional data analysis is a technique used to analyze vectors of unit-sum proportions, such as those obtained from soil sample studies or species abundance surveys. We summarized specimen staining patterns by the proportion of cells staining at mild, moderate, and intense levels and used compositional data analysis to summarize and compare the resulting staining profiles.

Results: In a study of Syndecan-1 staining patterns among 44 localized prostate cancer cases with Gleason score 7 disease, compositional data analysis did not detect a statistically significant difference between the staining patterns in recurrent (n = 22) versus nonrecurrent (n = 22) patients. Results indicated only modest increases in the proportion of cells staining at a moderate intensity in the recurrent group. In contrast, an analysis that compared quantitative scores across groups indicated a (borderline) significant increase in staining in the recurrent group (P = 0.05, t test).

Conclusions: Compositional data analysis offers a novel analytic approach for immunohistochemical studies, providing greater insight into differences in staining patterns between groups, but possibly lower statistical power than existing, score-based methods. When appropriate, we recommend conducting a compositional data analysis in addition to a standard score-based analysis.