bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Organochlorine Pesticide Residues and Risk of Testicular Germ Cell Carcinoma: A Population-Based Case-Control Study
Authors: Biggs Mary L. , Davis Mark D. , Eaton David L. , Weiss Noel S. , Barr Dana B. , Doody David R. , Fish Sherianne , Needham Larry L. , Chen Chu , Schwartz Stephen M.
Published: August 2008

Testicular germ cell carcinoma (TGCC) is the most common malignancy among men ages 20 to 34 years. Although the pathogenesis of TGCC is poorly understood, suboptimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess antiandrogenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p′-DDE, and whether the p,p′-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor gene. We conducted a population-based case-control study among 18- to 44-year-old male residents of three Washington State counties. Cases (n = 246) were diagnosed during 1999 to 2003 with a first, primary TGCC. Controls (n = 630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatography-high-resolution mass spectrometry analysis of organochlorine pesticide residues and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p′-DDE was modified by androgen receptor CAG (<23 versus ≥23 repeats) or GGN (<17 versus ≥17 repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2012–8)
Red Meat Consumption during Adolescence among Premenopausal Women and Risk of Breast Cancer
Authors: Linos Eleni , Willett Walter C. , Cho Eunyoung , Colditz Graham , Frazier Lindsay A.
Published: August 2008

Background: Adolescence may be a period of increased susceptibility to breast cancer due to regular division of undifferentiated cells that occurs between puberty and first birth. Red meat consumption during early adult life has been associated with breast cancer, but intake during adolescence has not been examined prospectively. We aimed to assess the relationship between red meat intake during adolescence and premenopausal breast cancer.

Methods: We examined the incidence of invasive premenopausal breast cancer prospectively within the Nurses' Health Study II. A total of 39,268 premenopausal women who completed a validated 124-item food frequency questionnaire on their diet during high school, were followed for 7 years, from 1998 to 2005. Cox proportional hazards regression was used to estimate relative risks (RR) and 95% confidence intervals (95% CI).

Results: 455 cases of invasive premenopausal breast cancer were diagnosed between 1998 and 2005. Compared with women in the lowest quintile of red meat intake during high school, the multivariate-adjusted RR for the highest quintile of intake was 1.34 (95% CI, 0.94-1.89; Ptrend = 0.05). A significant linear association was observed with every additional 100 g of red meat consumed per day (RR, 1.20; 95% CI, 1.00-1.43; P = 0.05). This association was more pronounced in hormone receptor–positive tumors (RR, 1.36; 95% CI, 1.08-1.70; P = 0.008) and was not significant in hormone receptor–negative tumors (RR, 0.99; 95% CI, 0.61-1.61, P = 0.97).

Conclusion: Higher red meat intake in adolescence may increase the risk of premenopausal breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2146–51)
Multiplex Genotyping as a Biomarker for Susceptibility to Carcinogenic Exposure in the FLEHS Biomonitoring Study
Authors: Ketelslegers Hans B. , Gottschalk Ralph W.H. , Koppen Gudrun , Schoeters Greet , Baeyens Willy F. , van Larebeke Nicolas A. , van Delft Joost H.M. , Kleinjans Jos C.S.
Published: August 2008

Cancer has been suggested to result from interactions between genetic and environmental factors, and certain subgroups in the general population may be at increased risk because of their relatively higher susceptibility to environmental carcinogens. The current study, part of a large biomonitoring study conducted in Flanders from 2002 to 2006 (The Flanders Environment and Health Survey), aims to determine these susceptible subpopulations based on multiple genotypic differences between individuals.

A random selection of 429 adolescents and 361 adults was genotyped for 36 polymorphisms in 23 genes selected because of their known role in carcinogen metabolism, DNA repair, and oxidative stress. In both age groups, relationships between endogenous exposure to organochloride substances (polychlorinated biphenyl, hexachlorobenzene, dichlorodiphenyl dichloroethane), metals (cadmium, lead), and urinary metabolites (1-hydroxypyrene, trans-trans muconic acid) versus genotoxic effects (Comet assay and micronuclei in lymphocytes, and urinary 8-hydroxydeoxyguanosine) were investigated. In addition, in the study among adults, the relationship of these exposures with several tumor markers (prostate-specific antigen, carcinoembryonic antigen, and p53) was tested. The impact of the genotype on established exposure-effect relationships was evaluated. Eight exposure-effect relationships were found, including three novel associations, with an impact of various genotypes, predominantly affecting biotransformation and oxidative stress response.

This study shows that at least part of the interindividual differences in relationships between carcinogen exposure and genotoxic effect can be explained by genotypic differences, enabling the identification of more susceptible subgroups for environmental cancer risks. This may be of relevance for environmental health policy setting. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1902–12)
Psychologic Predictors of Cancer Information Avoidance among Older Adults: The Role of Cancer Fear and Fatalism
Authors: Miles Anne , Voorwinden Sanne , Chapman Sarah , Wardle Jane
Published: August 2008

Little is known about the correlates of cancer information avoidance and whether people with negative feelings and beliefs about cancer are more likely to avoid cancer information, allowing such thoughts and feelings to persist unchallenged. Using the Extended Parallel Processing Model as a theoretical guide, we tested the hypothesis that cancer fear and fatalism would predict cancer information avoidance but that part of this effect would be mediated via cancer-specific threat and efficacy beliefs. A community sample of older adults, ages 50 to 70 years (n = 1,442), completed a postal questionnaire that included the Powe Fatalism Inventory and the Champion Cancer Fear scale along with other measures of cancer-specific beliefs and demographic variables. Higher levels of cancer fear were positively associated with higher levels of cancer information avoidance, and part of this relationship was mediated via perceived cancer severity. The relationship between cancer fatalism and cancer information avoidance was partly mediated by severity and response-efficacy beliefs. This research shows that people with negative views about cancer are more likely to avoid cancer information. This means people with higher levels of cancer fear and fatalism are less likely to learn about positive developments made in the field of cancer control, allowing such negative feelings and views to continue. Research needs to focus on how to get positive messages about improvements in cancer prevention and control through to people who are fearful of and fatalistic about the disease. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1872–9)
Disparities in Cervical Cancer Screening between Asian American and Non-Hispanic White Women
Authors: Wang Judy H. , Sheppard Vanessa B. , Schwartz Marc D. , Liang Wenchi , Mandelblatt Jeanne S.
Published: August 2008

Background: Asian American women have higher cervical cancer mortality rates than non-Hispanic White women, yet have lower Pap screening rates than their White counterparts. This study examined whether ethnic differences in the use of Pap screening were associated with differences in cultural views, controlling for demographic and access factors.

Methods: Cross-sectional survey data from the Commonwealth 2001 Health Care Quality Survey were used. Non-Hispanic White (n = 2,146) and Asian American women (including Chinese, Vietnamese, Korean, Filipino, and Japanese; n = 259) were included in this study. Eastern cultural views were measured by beliefs in the role of self-care and luck. Access factors (having health insurance, regular providers, and communication with providers) and demographics of patients and providers were measured. The outcome was receipt of a Pap test in the past 2 years.

Results: Asian American women had a lower rate of obtaining a recent Pap test (70%) than non-Hispanic White women (81%; P = 0.001). More Asians believed in the role of luck and self-care and experienced access barriers than Whites (P < 0.0001). Women with less Eastern cultural views are more likely to be recently screened than women with more (odds ratio, 1.08; 95% confidence interval, 1.00-1.16; P < 0.05). All access factors and provider gender types predicted the outcome. Within the Asian subgroups, Vietnamese women had lower screening rates (55%) and greater Eastern cultural views than their Asian counterparts.

Conclusion: More research is needed to understand cultural and other barriers to Pap screening in high-risk Asian women, and attention should be paid to within-group differences. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1968–73)
Reproducibility of Serum Pituitary Hormones in Women
Authors: Arslan Alan A. , Gu Yian , Zeleniuch-Jacquotte Anne , Koenig Karen L. , Liu Mengling , Velikokhatnaya Lyudmila , Shore Roy E. , Toniolo Paolo , Linkov Faina , Lokshin Anna E.
Published: August 2008

Endogenous pituitary hormones are commonly used in clinical and epidemiologic studies and some of them are thought to influence the risk of several diseases in women. In most studies, endogenous levels of pituitary hormones are usually assessed at a single point in time, assuming that this single measurement represents the long-term biomarker status of the individual. Such an assumption is rarely tested and may not always be valid. This study examined the reproducibility of the following pituitary hormones: adrenocorticotropic hormone (ACTH), growth hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin, measured using the Luminex xMap method in sera of healthy premenopausal and postmenopausal women. The study included 30 premenopausal women with three yearly samples and 35 postmenopausal women with two repeated yearly samples randomly selected from an existing prospective cohort. Analysis of intraclass correlation coefficients suggested higher reproducibility in postmenopausal women compared with premenopausal women for the following hormones: FSH (0.72 and 0.37, respectively), LH (0.83 and 0.44, respectively), and growth hormone (0.60 and 0.35, respectively). The intraclass correlation coefficients were relatively high and similar between postmenopausal and premenopausal women for ACTH (0.95 and 0.94, respectively), TSH (0.85 and 0.85, respectively), and prolactin (0.72 and 0.69, respectively). This study found that serum concentrations of FSH, LH, and growth hormone are stable in postmenopausal women and that ACTH, TSH, and prolactin are stable in both premenopausal and postmenopausal women, suggesting that a single measurement may reliably categorize average levels over at least a 2-year period. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1880–3)
Genetic Polymorphisms in the Paraoxonase 1 Gene and Risk of Ovarian Epithelial Carcinoma
Authors: Lurie Galina , Wilkens Lynne R. , Thompson Pamela J. , McDuffie Katharine E. , Carney Michael E. , Terada Keith Y. , Goodman Marc T.
Published: August 2008

Oxidative stress during successive ovulations increases the opportunity for DNA damage to ovarian epithelial cells and the potential for malignant transformation. Paraoxonase 1 (PON1) is an endogenous free radical scavenger that reduces oxidative stress. The association of two common functional single nucleotide polymorphisms (SNP), rs854560 T>A and rs662 A>G, with the risk of epithelial ovarian cancer was examined in a population-based case-control study in Hawaii. A personal interview and blood specimens were collected from 274 women with histologically confirmed, primary ovarian cancer and 452 controls frequency matched on age and ethnicity. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Both PON1 SNPs were significantly associated with ovarian cancer risk. The ORs were 0.53 (95% CI, 0.35-0.79; P for allele-dose effect = 0.01) for women carrying the rs854560 T allele compared with women with the AA genotype and 0.65 (95% CI, 0.44-0.95; P for allele-dose effect = 0.03) for women carrying the rs662 A allele compared with women with the GG genotype. The association of the rs854560 T genotype with risk was stronger among smokers (OR, 0.33; 95% CI, 0.17-0.64; P for allele-dose effect = 0.0007) than among nonsmokers (OR, 0.68; 95% CI, 0.40-1.18; P for allele-dose effect = 0.53). The decreased risk associated with the rs854560 T allele was also stronger among obese women (OR, 0.19; 95% CI, 0.06-0.55; P for allele-dose effect = 0.007) than among nonobese women (OR, 0.62; 95% CI, 0.40-0.98; P for allele-dose effect = 0.16). Our study provides evidence for an association of two PON1 SNPs with the risk of epithelial ovarian cancer. Possible effect modification of these associations by tobacco smoking and obesity needs confirmation in other studies. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2070–7)
The Human Papillomavirus Infection in Men Study: Human Papillomavirus Prevalence and Type Distribution among Men Residing in Brazil, Mexico, and the United States
Authors: Giuliano Anna R. , Lazcano-Ponce Eduardo , Villa Luisa L. , Flores Roberto , Salmeron Jorge , Lee Ji-Hyun , Papenfuss Mary R. , Abrahamsen Martha , Jolles Emily , Nielson Carrie M. , Baggio Maria Luisa , Silva Roberto , Quiterio Manuel
Published: August 2008

Male sexual behavior influences the rates of cervical dysplasia and invasive cervical cancer, as well as male human papillomavirus (HPV) infection and disease. Unfortunately, little is known regarding male HPV type distribution by age and across countries. In samples combined from the coronal sulcus, glans penis, shaft, and scrotum of 1,160 men from Brazil, Mexico, and the United States, overall HPV prevalence was 65.2%, with 12.0% oncogenic types only, 20.7% nononcogenic types only, 17.8% both oncogenic and nononcogenic, and 14.7% unclassified infections. Multiple HPV types were detected in 25.7% of study participants. HPV prevalence was higher in Brazil (72.3%) than in the United States (61.3%) and Mexico (61.9%). HPV16 (6.5%), HPV51 (5.3%), and HPV59 (5.3%) were the most commonly detected oncogenic infections, and HPV84 (7.7%), HPV62 (7.3%), and HPV6 (6.6%) were the most commonly detected nononcogenic infections. Overall HPV prevalence was not associated with age. However, significant associations with age were observed when specific categories of HPV, nononcogenic, and unclassified HPV infections were considered. Studies of HPV type distribution among a broad age range of men from multiple countries is needed to fill the information gap internationally with respect to our knowledge of HPV infection in men. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2036–43)
Alcohol and Breast Cancer Risk Defined by Estrogen and Progesterone Receptor Status: A Case-Control Study
Authors: Deandrea Silvia , Talamini Renato , Foschi Roberto , Montella Maurizio , Dal Maso Luigino , Falcini Fabio , La Vecchia Carlo , Franceschi Silvia , Negri Eva
Published: August 2008

Background: Alcohol consumption increases breast cancer risk. Some studies suggested that this association is stronger or limited to tumors expressing estrogen receptors (ER).

Methods: We investigated the role of alcohol according to ER and progesterone receptor (PR) status in a case-control study on breast cancer conducted from 1991 to 1994 in three Italian areas. Cases were 989 women with incident, histologically confirmed breast cancer. Controls were 1,350 women admitted to hospitals in the same catchment areas for acute nonneoplastic diseases. A validated food-frequency questionnaire was used to collect information on dietary habits and lifetime consumption of various alcoholic beverages. Multiple logistic regression models were used to estimate odds ratios and 95% confidence interval (95% CI).

Results: Alcohol drinking was associated with ER+ tumors (odds ratio, 2.16; 95% CI, 1.68-2.76 for an intake of ≥13.8 g/d as compared with nondrinkers). The odds ratio was 1.13 (95% CI, 1.07-1.20) for a 10-g increase in daily intake. For ER- tumors, the relation with alcohol consumption was not significant (odds ratio, 1.36; 95% CI, 0.93-2.01). When breast cancers were further classified according to PR, the findings for ER+PR+ cancers were similar to those for all ER+ ones, with an odds ratio of 2.34 (95% CI, 1.81-3.04) for an intake of ≥13.8 g/d. No significant association emerged for ER-PR- tumors (odds ratio, 1.25; 95% CI, 0.81-1.94).

Conclusion: This study supports the hypothesis that alcohol is more strongly related to ER+ than to ER- breast tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2025–8)
Dietary Soy and Isoflavone Intake and Risk of Colorectal Cancer in the Japan Public Health Center–Based Prospective Study
Authors: Akhter Munira , Inoue Manami , Kurahashi Norie , Iwasaki Motoki , Sasazuki Shizuka , Tsugane Shoichiro ,   for the Japan Public Health Center-Based Prospective Study Group
Published: August 2008

Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2128–35)
Body Size and Risk of Luminal, HER2-Overexpressing, and Triple-Negative Breast Cancer in Postmenopausal Women
Authors: Phipps Amanda I. , Malone Kathleen E. , Porter Peggy L. , Daling Janet R. , Li Christopher I.
Published: August 2008

Although the clinical relevance of molecular subtypes of breast cancer has been documented, little is known about risk factors for different tumor subtypes, especially the HER2-overexpressing and the triple-negative subtypes that have poor prognoses. Obesity may be differentially related to the risk of different subtypes given the various potential mechanisms underlying its association with breast cancer. We pooled two population-based case-control studies of postmenopausal breast cancer for an analysis, including 1,447 controls and 1,008 luminal (hormone receptor positive), 39 HER2-overexpressing (hormone receptor negative, HER2 positive), and 77 triple-negative (hormone receptor and HER2 negative) cases. Associations between anthropometric factors and the risk of different breast cancer subtypes were evaluated using polytomous logistic regression. Among women not currently using menopausal hormone therapy, body mass index (BMI) and weight were associated with the risk of luminal tumors [odds ratio (OR) comparing highest versus lowest quartiles, 1.7; 95% confidence interval (95% CI), 1.2-2.4 and OR, 1.7; 95% CI, 1.2-2.4, respectively] and suggestively associated with risk of triple-negative tumors (OR, 2.7; 95% CI, 1.0-7.5 and OR, 5.1; 95% CI, 1.1-23.0, respectively). Neither BMI nor weight was associated with the risk of any tumor subtype among hormone therapy users. The positive relationship between BMI and luminal tumors among postmenopausal women not using hormone therapy is well characterized in the literature. Although our sample size was limited, body size may also be related to the risk of postmenopausal triple-negative breast cancer among nonusers of hormone therapy. Given the expanding obesity epidemic, the widespread cessation of hormone therapy use, and the poor prognosis of triple-negative tumors, this novel finding merits confirmation. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2078–86)
Nested Case-Control Study of the Association of Circulating Levels of Serum Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 with Breast Cancer in Young Women in Norway
Authors: Vatten Lars J. , Holly Jeff M. , Gunnell David , Tretli Steinar
Published: August 2008

Background: High circulating levels of insulin-like growth factor (IGF-I) may elevate the risk of breast cancer in premenopausal women, possibly by increasing cell proliferation and reducing apoptosis.

Methods: We conducted a nested case-control study among 35,105 Norwegian women who participated in a health screening survey, ages 40 to 42 years, and who were subsequently followed for a mean period of 4.3 years. During this period, 325 women were diagnosed with breast cancer; 647 women without breast cancer, matched on age and time of blood sampling, were selected as controls. Serum concentrations of IGF-I and its main binding protein (IGFBP-3) were measured with radioimmunoassay, and logistic regression analysis was used to adjust for relevant covariates.

Results: The mean age at blood collection was 41.1 years in both groups, and the mean age at diagnosis for the cases was 45.4 years (range, 40-51 years). The median IGF-I level did not differ between cases (205 ng/mL) and controls (202 ng/mL). When analyzed by categories of serum IGF-I, the relative risk for women in the highest versus the lowest quintile was 1.46 (95% confidence interval, 0.93-2.32; Ptrend = 0.15) after adjusting for serum IGFBP-3, age, and year of blood collection. The exclusion of cases that were diagnosed within 2 years after blood collection did not materially affect the results.

Conclusion: We found only a modest positive association between serum IGF-I levels and risk of breast cancer in women younger than 50 years of age. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2097–100)
Salt and Gastric Adenocarcinoma: A Population-Based Cohort Study in Norway
Authors: Sjödahl Krister , Jia Chongqi , Vatten Lars , Nilsen Tom , Hveem Kristian , Lagergren Jesper
Published: August 2008

Background: Gastric adenocarcinoma is the second leading cause of cancer death worldwide. It has been suggested that consumption of salted foods is associated with increased risk of this cancer, but the results of the few available prospective studies are contradictory.

Methods: A population-based, prospective cohort study in Nord-Trondelag County in Norway during 1984 to 2002 addressed dietary salt intake in relation to risk of gastric adenocarcinoma. In 1984 to 1986, all adult county residents were invited to a health survey in which participants answered questionnaires concerning dietary salt intake and other factors. Gastric adenocarcinomas were identified in the Norwegian Cancer Registry. Relative risks were calculated using Cox proportional hazards regression models, adjusted for potentially confounding factors.

Results: Follow-up of 1,122,765 person-years at risk among 73,133 cohort members disclosed 313 incident cases of gastric adenocarcinomas occurring at least 3 years after inclusion into the cohort. There were no statistically significant associations between different levels of salt intake and risk of gastric adenocarcinoma. High consumers of dietary salt were not at increased risk of developing gastric adenocarcinoma compared with low consumers (hazard ratio, 1.0; 95% confidence interval, 0.7-1.4), and no dose-response effect was observed (Ptrend = 0.55).

Conclusion: High intake of dietary salt does not appear to increase the risk of gastric adenocarcinoma in this low-incidence western population. (Cancer Epidemiol Biomarkers Prev 2008;17(8):1997–2001)
Breast Cancer Risk Polymorphisms and Interaction with Ionizing Radiation among U.S. Radiologic Technologists
Authors: Bhatti Parveen , Doody Michele M. , Alexander Bruce H. , Yuenger Jeff , Simon Steven L. , Weinstock Robert M. , Rosenstein Marvin , Stovall Marilyn , Abend Michael , Preston Dale L. , Pharoah Paul , Struewing Jeffery P. , Sigurdson Alice J.
Published: August 2008

Genome-wide association studies are discovering relationships between single-nucleotide polymorphisms and breast cancer, but the functions of these single-nucleotide polymorphisms are unknown and environmental exposures are likely to be important. We assessed whether breast cancer risk single-nucleotide polymorphisms interacted with ionizing radiation, a known breast carcinogen, among 859 cases and 1,083 controls nested in the U.S. Radiologic Technologists cohort. Among 11 Breast Cancer Association Consortium risk single-nucleotide polymorphisms, we found that the genotype-associated breast cancer risk varied significantly by radiation dose for rs2107425 in the H19 gene (Pinteraction = 0.001). H19 is a maternally expressed imprinted mRNA that is closely involved in regulating the IGF2 gene and could exert its influence by this or by some other radiation-related pathway. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2007–11)
Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States
Authors: Kastrinos Fay , Stoffel Elena M. , Balmaña Judith , Steyerberg Ewout W. , Mercado Rowena , Syngal Sapna
Published: August 2008

Background and Aims: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression.

Methods: This is a cross-sectional prevalence study of 1,914 unrelated probands undergoing clinical genetic testing for MLH1 and MSH2 mutations at a commercial laboratory.

Results: Fifteen percent (285 of 1,914) of subjects had pathogenic mutations (112 MLH1, 173 MSH2). MLH1 carriers had a higher prevalence of colorectal cancer (79% versus 69%, P = 0.08) and younger mean age at diagnosis (42.2 versus 44.8 years, P = 0.03) than MSH2 carriers. Forty-one percent of female carriers had endometrial cancer and prevalence was similar in both groups. Other cancers were more frequent in MSH2 carriers (24% versus 9%, P = 0.001) and their families (P < 0.001). Multivariable analyses confirmed these associations. Of the 1,016 subjects who underwent Southern blot analysis, 42 had large rearrangements (7 MLH1, 35 MSH2). There were no phenotypic differences between carriers with large rearrangements and point mutations.

Conclusions: In this large study of mismatch repair gene mutation carriers from the United States, MLH1 carriers had more colorectal cancer than MSH2 carriers whereas endometrial cancer prevalence was similar. Large genomic rearrangements were more frequent in the MSH2 gene. MSH2 carriers and their relatives have more extracolonic nonendometrial Lynch syndrome–associated cancers and may benefit from additional screening. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2044–51)
Association between Common Genetic Variation in Cockayne Syndrome A and B Genes and Nucleotide Excision Repair Capacity among Smokers
Authors: Leng Shuguang , Bernauer Amanda , Stidley Christine A. , Picchi Maria A. , Sheng Xin , Frasco Melissa A. , Van Den Berg David , Gilliland Frank D. , Crowell Richard E. , Belinsky Steven A.
Published: August 2008

Mutagen sensitivity in in vitro cultured lymphocytes challenged by benzo[a]pyrene diolepoxide (BPDE) has been validated as an intrinsic susceptibility factor for several cancers. Bulky BPDE-DNA adducts are repaired via either transcription-coupled repair or global genome nucleotide excision repair depending on the location of lesions. Cockayne syndrome A (CSA) and B (CSB) play essential roles in integrating the recognition of damage, chromatin remodeling, and the core nucleotide excision repair proteins. This study evaluated the hypothesis that common genetic variation in CSA and CSB is associated with mutagen sensitivity induced by BPDE in 276 cancer-free smokers. Tag single nucleotide polymorphisms (SNP; n = 37) selected across the entire coding and putative regulatory regions of CSA and CSB based on a high-density SNP database were genotyped by the Illumina Golden Gate assay. Major principal components of CSA and CSB that captured the linkage disequilibrium from multiple SNPs were globally associated with the number of breaks per cell at the threshold of 80% (P ≤ 0.02 for both genes). Haplotype H125 in CSA and H97 in CSB as well as SNPs in high linkage disequilibrium with these two haplotypes were significantly associated with a 13% to 15% reduction in the mean number of chromatid breaks per cell (P < 0.05). A resampling-based omnibus test supported the significant association between SNPs and haplotypes in CSA and mutagen sensitivity induced by BPDE (P = 0.035). This study implicates transcription-coupled repair in protecting the cell from BPDE-induced DNA damage. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2062–9)
Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium
Authors: Kote-Jarai Zsofia , Easton Douglas F. , Stanford Janet L. , Ostrander Elaine A. , Schleutker Johanna , Ingles Sue A. , Schaid Daniel , Thibodeau Stephen , Dörk Thilo , Neal David , Cox Angela , Maier Christiane , Vogel Walter , Guy Michelle , Muir Kenneth , Lophatananon Artitaya , Kedda Mary-Anne , Spurdle Amanda , Steginga Suzanne , John Esther M. , Giles Graham , Hopper John , Chappuis Pierre O. , Hutter Pierre , Foulkes William D. , Hamel Nancy , Salinas Claudia A. , Koopmeiners Joseph S. , Karyadi Danielle M. , Johanneson Bo , Wahlfors Tiina , Tammela Teuvo L. , Stern Mariana C. , Corral Roman , McDonnell Shannon K. , Schürmann Peter , Meyer Andreas , Kuefer Rainer , Leongamornlert Daniel A. , Tymrakiewicz Malgorzata , Liu Jo-fen , O'Mara Tracy , Gardiner R.A. (Frank) , Aitken Joanne , Joshi Amit D. , Severi Gianluca , English Dallas R. , Southey Melissa , Edwards Stephen M. , Al Olama Ali Amin ,   The PRACTICAL Consortium, Eeles Rosalind A.
Published: August 2008

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)
The Multifunctional Protein Glyceraldehyde-3-Phosphate Dehydrogenase Is Both Regulated and Controls Colony-Stimulating Factor-1 Messenger RNA Stability in Ovarian Cancer
Authors: Zhou Yi , Yi Xiaofang , Stoffer Jha'Nae B. , Bonafe Nathalie , Gilmore-Hebert Maureen , McAlpine Jessica , Chambers Setsuko K.
Published: August 2008

Although glyceraldehyde-3-phosphate dehydrogenase's (GAPDH) predilection for AU-rich elements has long been known, the expected connection between GAPDH and control of mRNA stability has never been made. Recently, we described GAPDH binding the AU-rich terminal 144 nt of the colony-stimulating factor-1 (CSF-1) 3′ untranslated region (UTR), which we showed to be an mRNA decay element in ovarian cancer cells. CSF-1 is strongly correlated with the poor prognosis of patients with ovarian cancer. We investigated the functional significance of GAPDH's association with CSF-1 mRNA and found that GAPDH small interfering RNA reduces both CSF-1 mRNA and protein levels by destabilizing CSF-1 mRNA. CSF-1 mRNA half-lives were decreased by 50% in the presence of GAPDH small interfering RNA. RNA footprinting analysis of the 144 nt CSF-1 sequence revealed that GAPDH associates with a large AU-rich–containing region. The effects of binding of GAPDH protein or ovarian extracts to mutations of the AU-rich regions within the footprint were consistent with this finding. In a tissue array containing 256 ovarian and fallopian tube cancer specimens, we found that GAPDH was regulated in these cancers, with almost 50% of specimens having no GAPDH staining. Furthermore, we found that low GAPDH staining was associated with a low CSF-1 score (P = 0.008). In summary, GAPDH, a multifunctional protein, now adds regulation of mRNA stability to its repertoire. We are the first to evaluate the clinical role of GAPDH protein in cancer. In ovarian cancers, we show that GAPDH expression is regulated, and we now recognize that one of the many functions of GAPDH is to promote mRNA stability of CSF-1, an important cytokine in tumor progression. (Mol Cancer Res 2008;6(8):1375–84)
Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor-α Expression in Breast Cancer Cells
Authors: Han Youqi , Yang Lin , Suarez-Saiz Fernando , San-Marina Serban , Cui Jie , Minden Mark D.
Published: August 2008

The antiestrogen tamoxifen has been used in the treatment of hormone-responsive breast cancer for over a decade. The loss of estrogen receptor (ER) expression is the most common mechanism for de novo antiestrogen resistance. Wilms' tumor 1 suppressor gene (WT1) is a clinically useful marker that is associated with poor prognosis in breast cancer patients; its high level expression is frequently observed in cases of breast cancer that are estrogen and progesterone receptor negative. The lack of expression of these receptors is characteristic of tumor cells that are not responsive to hormonal manipulation. To determine whether there is a linkage between WT1 expression and antiestrogen resistance in breast cancer cells, we studied the effect of WT1 on tamoxifen responsiveness in ERα-positive MCF-7 cells. We found that overexpression of WT1 in MCF-7 markedly abrogated tamoxifen-induced cell apoptosis and 17β-estradiol (E2)–mediated cell proliferation. The expressions of ERα and its downstream target genes were significantly repressed following overexpression of WT1, whereas the down-regulation of WT1 by WT1 shRNA could enhance ERα expression and the sensitivity to tamoxifen treatment in ERα-negative MDA468 and HCC1954 cells that express high levels of WT1. Furthermore, we have confirmed that the WT1 protein can bind to endogenous WT1 consensus sites in the proximal promoter of ERα and thus inhibit the transcriptional activity of the ERα promoter in a WT1 site sequence–specific manner. Our study clearly implicates WT1 as a mediator of antiestrogen resistance in breast cancer through down-regulation of ERα expression and supports the development of WT1 inhibitors as a potential means of restoring antiestrogen responsiveness in breast cancer therapy. (Mol Cancer Res 2008;6(8):1347–55)
Protein Sialylation by Sialyltransferase Involves Radiation Resistance
Authors: Lee Minyoung , Lee Hae-June , Bae Sangwoo , Lee Yun-Sil
Published: August 2008

Previously, we identified β-galactoside α(2,6)-sialyltransferase (ST6Gal I) as a candidate biomarker for ionizing radiation. The expression of ST6Gal I and the level of protein sialylation increased following radiation exposure in a dose-dependent manner. Radiation induced ST6Gal I cleavage and the cleaved form of ST6Gal I was soluble and secreted. Sialylation of integrin β1, a glycosylated cell surface protein, was stimulated by radiation exposure and this increased its stability. Overexpression of ST6Gal I in SW480 colon cancer cells that initially showed a low level of ST6Gal I expression increased the sialylation of integrin β1 and also increased the stability of the protein. Inhibition of sialylation by transfection with neuraminidase 2 or neuraminidase 3 or by treatment with short interfering RNA targeting ST6Gal I reversed the effects of ST6Gal I overexpression. In addition, ST6Gal I overexpression increased clonogenic survival following radiation exposure and reduced radiation-induced cell death and caspase 3 activation. However, removal of sialic acids by neuraminidase 2 or knockdown of expression by short interfering RNA targeting ST6Gal I restored radiation-induced cell death phenotypes. In conclusion, radiation exposure was found to increase the sialylation of glycoproteins such as integrin β1 by inducing the expression of ST6Gal I, and increased protein sialylation contributed to cellular radiation resistance. (Mol Cancer Res 2008;6(8):1316–25)
Stress Chaperone GRP78/BiP Confers Chemoresistance to Tumor-Associated Endothelial Cells
Authors: Virrey Jenilyn J. , Dong Dezheng , Stiles Caryn , Patterson John B. , Pen Ligaya , Ni Min , Schönthal Axel H. , Chen Thomas C. , Hofman Florence M. , Lee Amy S.
Published: August 2008

The tumor vasculature is essential for tumor growth and survival and is a key target for anticancer therapy. Glioblastoma multiforme, the most malignant form of brain tumor, is highly vascular and contains abnormal vessels, unlike blood vessels in normal brain. Previously, we showed that primary cultures of human brain endothelial cells, derived from blood vessels of malignant glioma tissues (TuBEC), are physiologically and functionally different from endothelial cells derived from nonmalignant brain tissues (BEC) and are substantially more resistant to apoptosis. Resistance of TuBEC to a wide range of current anticancer drugs has significant clinical consequences as it represents a major obstacle toward eradication of residual brain tumor. We report here that the endoplasmic reticulum chaperone GRP78/BiP is generally highly elevated in the vasculature derived from human glioma specimens, both in situ in tissue and in vitro in primary cell cultures, compared with minimal GRP78 expression in normal brain tissues and blood vessels. Interestingly, TuBEC constitutively overexpress GRP78 without concomitant induction of other major unfolded protein response targets. Resistance of TuBEC to chemotherapeutic agents such as CPT-11, etoposide, and temozolomide can be overcome by knockdown of GRP78 using small interfering RNA or chemical inhibition of its catalytic site. Conversely, overexpression of GRP78 in BEC rendered these cells resistant to drug treatments. Our findings provide the proof of principle that targeting GRP78 will sensitize the tumor vasculature to chemotherapeutic drugs, thus enhancing the efficacy of these drugs in combination therapy for glioma treatment. (Mol Cancer Res 2008;6(8):1268–75)
Bortezomib-Resistant Nuclear Factor-κB Activity in Multiple Myeloma Cells
Authors: Markovina Stephanie , Callander Natalie S. , O'Connor Shelby L. , Kim Jihoon , Werndli Jae E. , Raschko Martha , Leith Catherine P. , Kahl Brad S. , Kim KyungMann , Miyamoto Shigeki
Published: August 2008

Bortezomib (Velcade/PS341), a proteasome inhibitor used in the treatment of multiple myeloma (MM), can inhibit activation of nuclear factor-κB (NF-κB), a family of transcription factors often deregulated and constitutively activated in primary MM cells. NF-κB can be activated via several distinct mechanisms, including the proteasome inhibitor–resistant (PIR) pathway. It remains unknown what fraction of primary MM cells harbor constitutive NF-κB activity maintained by proteasome-dependent mechanisms. Here, we report an unexpected finding that constitutive NF-κB activity in 10 of 14 primary MM samples analyzed is refractory to inhibition by bortezomib. Moreover, when MM cells were cocultured with MM patient-derived bone marrow stromal cells (BMSC), microenvironment components critical for MM growth and survival, further increases in NF-κB activity were observed that were also refractory to bortezomib. Similarly, MM-BMSCs caused PIR NF-κB activation in the RPMI8226 MM cell line, leading to increased NF-κB–dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells frequently harbor PIR NF-κB activity that is further enhanced by the presence of patient-derived BMSCs. They also suggest that this activity is likely relevant to the drug resistance development in some patients. Further elucidation of the mechanism of PIR NF-κB regulation could lead to the identification of novel diagnostic biomarkers and/or therapeutic targets for MM treatment. (Mol Cancer Res 2008;6(8):1356–64)
Alternative Splicing and Caspase-Mediated Cleavage Generate Antagonistic Variants of the Stress Oncoprotein LEDGF/p75
Authors: Brown-Bryan Terry A. , Leoh Lai S. , Ganapathy Vidya , Pacheco Fabio J. , Mediavilla-Varela Melanie , Filippova Maria , Linkhart Thomas A. , Gijsbers Rik , Debyser Zeger , Casiano Carlos A.
Published: August 2008

There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium–derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress–induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis. LEDGF/p75 has a COOH-terminally truncated splice variant, p52, whose role in stress survival and apoptosis has not been thoroughly investigated. We observed unbalanced expression of these proteins in a panel of tumor cell lines, with LEDGF/p75 generally expressed at higher levels. During apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the NH2-terminal PWWP domain and failed to transactivate the Hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of LEDGF/p75. Overexpression of p52 or its variants with truncated PWWP domains in several tumor cell lines induced apoptosis, an activity that was linked to the presence of an intron-derived COOH-terminal sequence. These results implicate the PWWP domain of p52 in transcription function but not in chromatin association and proapoptotic activities. Consistent with their unbalanced expression in tumor cells, LEDGF/p75 and p52 seem to play antagonistic roles in the cellular stress response and could serve as targets for novel antitumor therapies. (Mol Cancer Res 2008;6(8):1293–307)
Pneumothorax
Authors: Noppen Marc , De Keukeleire Tom
Published: August 2008

Pneumothorax represents a common clinical problem. An overview of relevant and updated information on epidemiology, pathophysiology, and management of spontaneous (primary and secondary), catamenial, and traumatic (iatrogenic and noniatrogenic) pneumothorax is given.
Old Meets Modern: The Use of Traditional Cryoprobes in the Age of Molecular Biology
Authors: Hetzel Jürgen , Hetzel Martin , Hasel Cornelia , Moeller Peter , Babiak Alexander
Published: August 2008

Background: Endobronchial forceps biopsies are often small and are associated with a relevant extent of artifacts. To overcome these limitations is an important task. Especially when considering predictive factors for pharmacological therapies of lung cancer (ERCC1, RRM1) a development of biopsy techniques seems to be essential. This is the first report on a new endobronchial biopsy technique called cryobiopsy. Objectives: In this study the feasibility and the potential advantages of applying cryoprobes for harvesting samples for histological examination in flexible bronchoscopies will be focused on. Methods: In 12 patients suffering from exophytic endobronchial malignancies, a modified flexible cryoprobe was used for immediate recanalization. The extracted tissue was examined histologically regarding sample quality and sample size. Results: Tissue samples obtained using the cryoprobe showed an extraordinary good quality in terms of size (median diameter of 6.7 mm, range 4.2–13 mm) and artifact-free sample area (75% of the samples showed an artifact-free sample area of more than 75%). Additionally molecular markers were shown to be well preserved. Conclusions: The new technique termed cryobiopsy might widen the chest physician’s range of tools for diagnostic bronchoscopies.