Umaima Al-Alem

Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort

BACKGROUND The relationships between cockroach and mouse allergen exposure, anti-cockroach and anti-mouse IgE, and wheeze, rhinitis, and atopic dermatitis in children as young as age 3 years are of public health importance but have not been thoroughly evaluated. OBJECTIVE We hypothesized that inner-city children might have anti-cockroach and anti-mouse IgE by age 3 years, and their presence would be associated with respiratory and atopic symptoms. METHODS Children were followed prospectively from birth through age 3 years (n = 404). Residential levels of cockroach and mouse allergens, sera levels of anti-cockroach and anti-mouse IgE, and parental report of wheeze, rhinitis, and atopic dermatitis were measured. RESULTS The odds of early wheeze were significantly higher among children who had IgE to cockroach (odds ratio [OR], 3.3; 95% CI, 1.8-6.2), mouse (OR, 4.6; 95% CI, 2.3-9.0), or both (OR, 9.7; 95% CI, 3.4-27.3). The odds of rhinitis or atopic dermatitis were also higher among children with IgE to cockroach, mouse, or both. Higher IgE class to cockroach and mouse was associated with wheeze and atopic dermatitis (tests for trend, P < .002). CONCLUSIONS Children age 2 to 3 years who have anti-cockroach and anti-mouse IgE are at increased risk of wheeze and atopy. Moreover, a dose-response relationship was found between higher IgE class and increased prevalence of wheeze, rhinitis, or atopic dermatitis. These findings indicate the importance of reducing exposure to cockroach and mouse allergens for susceptible children.

Occupational Exposure to Asbestos and Ovarian Cancer: A Meta-analysis

Objective: A recent Monographs Working Group of the International Agency for Research on Cancer (IARC) concluded that there is sufficient evidence for a causal association between exposure to asbestos and ovarian cancer. We performed a meta-analysis to quantitatively evaluate this association. Data sources: Searches of PubMed and unpublished data yielded a total of 18 cohort studies of women occupationally exposed to asbestos. Data extraction: Two authors independently abstracted data; any disagreement was resolved by consulting a third reviewer. Data synthesis: All but one study reported standardized mortality ratios (SMRs) comparing observed numbers of deaths with expected numbers for the general population; the exception was a study that reported standardized incidence ratios. For simplicity, we refer to all effect estimates as SMRs. The overall pooled SMR estimate for ovarian cancer was 1.77 (95% confidence interval, 1.37–2.28), with a moderate degree of heterogeneity among the studies (I2 = 35.3%, p = 0.061). Effect estimates were stronger for cohorts compensated for asbestosis, cohorts with estimated lung cancer SMRs > 2.0, and studies conducted in Europe compared with other geographic regions. Effect estimates were similar for studies with and without pathologic confirmation, and we found no evidence of publication bias (Egger’s test p-value = 0.162). Conclusions: Our study supports the IARC conclusion that exposure to asbestos is associated with increased risk of ovarian cancer.

Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation

BackgroundBreast cancer formation is associated with frequent changes in DNA methylation but the extent of very early alterations in DNA methylation and the biological significance of cancer-associated epigenetic changes need further elucidation.MethodsPyrosequencing was done on bisulfite-treated DNA from formalin-fixed, paraffin-embedded sections containing invasive tumor and paired samples of histologically normal tissue adjacent to the cancers as well as control reduction mammoplasty samples from unaffected women. The DNA regions studied were promoters (BRCA1, CD44, ESR1, GSTM2, GSTP1, MAGEA1, MSI1, NFE2L3, RASSF1A, RUNX3, SIX3 and TFF1), far-upstream regions (EN1, PAX3, PITX2, and SGK1), introns (APC, EGFR, LHX2, RFX1 and SOX9) and the LINE-1 and satellite 2 DNA repeats. These choices were based upon previous literature or publicly available DNA methylome profiles. The percent methylation was averaged across neighboring CpG sites.ResultsMost of the assayed gene regions displayed hypermethylation in cancer vs. adjacent tissue but the TFF1 and MAGEA1 regions were significantly hypomethylated (p ≤0.001). Importantly, six of the 16 regions examined in a large collection of patients (105 – 129) and in 15-18 reduction mammoplasty samples were already aberrantly methylated in adjacent, histologically normal tissue vs. non-cancerous mammoplasty samples (p ≤0.01). In addition, examination of transcriptome and DNA methylation databases indicated that methylation at three non-promoter regions (far-upstream EN1 and PITX2 and intronic LHX2) was associated with higher gene expression, unlike the inverse associations between cancer DNA hypermethylation and cancer-altered gene expression usually reported. These three non-promoter regions also exhibited normal tissue-specific hypermethylation positively associated with differentiation-related gene expression (in muscle progenitor cells vs. many other types of normal cells). The importance of considering the exact DNA region analyzed and the gene structure was further illustrated by bioinformatic analysis of an alternative promoter/intron gene region for APC.ConclusionsWe confirmed the frequent DNA methylation changes in invasive breast cancer at a variety of genome locations and found evidence for an extensive field effect in breast cancer. In addition, we illustrate the power of combining publicly available whole-genome databases with a candidate gene approach to study cancer epigenetics.

Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation.

Genistein has protective effects against prostate cancer (PCa) but whether this protection involves an estrogen receptor (ER) β dependent mechanism has yet to be elucidated. ER-β has a tumor suppressor role in PCa and its levels decline with cancer progression which was linked to ER-β promoter hypermethylation. Genistein has been suggested to have demethylating activities in cancer. However, the ability of genistein to reverse ER-β promoter hypermethylation in PCa has not been studied. In addition, there are great discrepancies among studies that examined the effect of genistein on ER-β gene expression. Therefore, we sought to explore effects of genistein on ER-β promoter methylation as a mechanism of modulating ER-β expression using three PCa cell lines, LNCaP, LAPC-4 and PC-3. We also examined the role of ER-β in mediating the preventive action of genistein. Our data demonstrated that genistein at physiological ranges (0.5-10 μmol/L) reduced ER-β promoter methylation significantly with corresponding dose-dependent increases in ER-β expression in LNCaP and LAPC-4 but not in PC-3 cells, which could be attributed to the low basal levels of ER-β promoter methylation in PC-3 cell line. Genistein induced phosphorylation, nuclear translocation and transcriptional activity of ER-β in all three PCa cell lines. Inhibitory effects of genistein on LAPC-4 and PC-3 cell proliferation were diminished using a specific ER-β antagonist. In conclusion, genistein and ER-β act together to prevent PCa cell proliferation; genistein increases ER-β levels via reducing its promoter methylation and ER-β, in turn, mediates the preventive action of genistein.

Allergies and Adult Gliomas: Cohort Results Strengthen Evidence for a Causal Association

The evidence for an association between a history of allergies and a reduced risk of glioma has been emerging (1). In this issue of the Journal, Calboli et al. (2) analyze associations between prediagnostic plasma immunoglobulin E (IgE) levels and the risk of adult glioma by combining data from four large prospective cohort studies. The pooled data resulted in a modest number of 169 glioma cases, but for a rare disease, this is a substantial contribution to the literature. A statistically significant protective association with borderline elevated levels of total IgE (25–100 kU/L) relative to clinically normal levels ( 100 kU/L) was not observed. The findings are somewhat perplexing, but further our understanding of the biological underpinnings of the protection that allergies appear to provide in the development of brain tumors. The results of Calboli et al. (2) are consistent with one other cohort study that reported a statistically significant inverse associ ation between risk of glioma and borderline elevated levels of IgE, but inconsistent associations with elevated IgE levels (3). This study (2) estimated an odds ratio (OR) near unity at elevated total IgE levels, whereas Schlehofer et al. (3) reported a protective association with elevated levels of respiratory allergen–specific IgE. They observed that the higher the level of respiratory allergen– specific IgE, the stronger was the association, and an increased association was statistically significant in patients with high grade glioma (3). Together, these studies point to an association between prediagnosis IgE level and risk of glioma, but the biological mechanism underlying this association is still unclear. The suggestion that allergies may be associated with a reduced risk of developing of brain tumors was made in the early 1990s (4). Since then, 10 case–control and two cohort studies have investigated this association using self-reported data on the history of allergic conditions. Results showed an inverse association of glioma risk with any allergic conditions compared with nonallergic conditions (pooled estimated OR = 0.60, 95% confidence interval [CI] = 0.52 to 0.69) (1). The association was statistically significant when limited to asthma, eczema, and hay fever as a group, and the association remained when consideration of proxy reporting was introduced in the analysis (1). These estimates based on self-report of allergies are similar to that observed by Calboli et al. (2) (total IgE 25–100 vs <25 kU/L, OR = 0.63, 95% CI = 0.42 to 0.93).

Association of genetic ancestry with breast cancer in ethnically diverse women from Chicago.

Introduction Non-Hispanic (nH) Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors. Methods We used a panel of 100 ancestry informative markers (AIMs) to estimate individual genetic ancestry in 656 women from the “Breast Cancer Care in Chicago” study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities. Results As expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54–0.92) among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56–0.95) among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02) and higher grade (p = 0.012) in nH Whites and later stage (p = 0.03) in nH Blacks. Conclusion Non-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups.

Zinc Intake and Risk of Prostate Cancer: Case-Control Study and Meta-Analysis.

Zinc is an essential dietary element that has been implicated in the pathogenesis of prostate cancer, a cancer that disproportionately affects men of African descent. Studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. Furthermore, very little is known about the relationship between zinc intake and prostate cancer among African Americans. We examined the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study of African Americans. We then compared our results with previous studies by performing a meta-analysis to summarize the evidence regarding the association between zinc and prostate cancer. Newly diagnosed African American men with histologically confirmed prostate cancer (n = 127) and controls (n = 81) were recruited from an urban academic urology clinic in Washington, DC. Controls had higher zinc intake, with a mean of 14 mg/day versus 11 mg/day for cases. We observed a non-significant, non-linear increase in prostate cancer when comparing tertiles of zinc intake (OR <6.5 vs 6.5–12.5mg/day 1.8, 95% CI: 0.6,5.6; OR <6.5 vs >12.5mg/day 1.3, 95% CI: 0.2,6.5). The pooled estimate from 17 studies (including 3 cohorts, 2 nested case-control, 11 case-control studies, and 1 randomized clinical trial, with a total of 111,199 participants and 11,689 cases of prostate cancer) was 1.07hi vs lo 95% CI: 0.98–1.16. Using a dose-response meta-analysis, we observed a non-linear trend in the relationship between zinc intake and prostate cancer (p for nonlinearity = 0.0022). This is the first study to examine the relationship between zinc intake in black men and risk of prostate cancer and systematically evaluate available epidemiologic evidence about the magnitude of the relationship between zinc intake and prostate cancer. Despite of the lower intake of zinc by prostate cancer patients, our meta-analysis indicated that there is no evidence for an association between zinc intake and prostate cancer.

Abstract 5569: Ki67 is an independent prognostic marker in breast cancer even after accounting for molecular subtype

Ki67 labeling index (LI) has been demonstrated to be a prognostic marker in invasive breast cancer; a high Ki67 LI is associated with poorer survival among breast cancer patients. The goal of these analyses was to examine the extent to which Ki67 was associated with specific breast cancer subtypes, and whether it could serve as an additional prognostic marker above and beyond breast cancer subtype, in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American). IHC analysis was performed on tissue microarrays constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study (patients diagnosed between 2005-2008). Tissue samples were tested for the expression of estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR and CK5/6. From these results, breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). TN tumors were subclassified into basal like (BL) if they expressed either EGFR or CK5/6 or otherwise classified as unspecified (US) if negative for both EGFR and CK5/6. Ki67 LI was classified as low ( In adjusted models, the proportion of tumors with a high Ki67 LI was much lower for luminal A (28%) than for luminal B, HER2, TN-US, and TN-BL subtypes (91,66, 77 and 89%, respectively, p In this multi-ethnic sample of breast cancer patients, we found that Ki67 was a significant independent predictor of more aggressive, higher grade disease, even after accounting for molecular subtype. Ki67 might serve as a useful additional marker for the classification of breast cancer into molecular subtypes. Citation Format: Abeer M. Mahmoud, Virgilia Macias, Umaima Al-alem, Jacob K. Kresovich, Galina Khramtsova, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Ki67 is an independent prognostic marker in breast cancer even after accounting for molecular subtype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2014-5569

Abstract A91: Does psychosocial stress play a role in the etiology of aggressive breast cancer? A cross-sectional study

Background: Greater levels of fear, anxiety or isolation (psychosocial stress) have been hypothesized to negatively alter the sympathetic-parasympathetic autonomic nervous system and suppress immune function, physiologic effects that in turn might impact breast tumor aggressiveness. There is a paucity of cohort data relating psychosocial stress to breast tumor aggressiveness. We examined associations between patient-reported psychosocial stress with aggressive breast cancer in a cross-sectional study of 989 recently diagnosed breast cancer patients (397 non-Hispanic white, 411 non-Hispanic black, 181 Hispanic). We examined associations of psychosocial stress with breast cancer aggressiveness and whether racial/ethnic differences in psychosocial stress might account for disparities in breast cancer aggressiveness. A major assumption of these analyses was that patients reporting greater psychosocial stress at interview (2–3 months after diagnosis) would have also reported relatively greater psychosocial stress had they been interviewed prior to diagnosis. Methods: Psychosocial stress was assessed using the Cohen perceived stress 4 item subscale, the UCLA felt loneliness scale (3 items), and the Cockburn psychological consequences scale (12 items). These three scales loaded onto a single factor in factor analysis, and were used to create a single, standardized psychosocial stress score (Cronbach9s alpha=0.56). Breast cancer aggressiveness was defined as Hormone (estrogen and progesterone) receptor negative tumors and tumors high in histologic grade. Differences in psychosocial stress scores were evaluated via t-tests, and logistic regression was used to estimate odds ratios for breast cancer aggressiveness corresponding to a one standard deviation increase in psychosocial stress score. All reported p-values are two-sided. Because aggressive breast cancer tends to lead to a later stage at diagnosis and an earlier age at diagnosis, adjustment for these variables may inappropriately attenuate the association of interest between psychosocial stress and tumor aggressiveness. Nonetheless, because psychosocial stress was measured after diagnosis, we adjusted for age and stage in some models. Results: Patient reported psychosocial stress was one-third of a standard deviation higher for patients with receptor negative vs. positive disease (mean score difference = 0.32, p=0.0003), and higher for patients with high vs. low or intermediate grade disease (difference = 0.17, p=0.03). Compared to nH-Whites, psychosocial stress scores were higher for nh-Black patients (difference = 0.22, p=0.006), and higher for Hispanic patients (difference = 0.44, p Conclusions: In this cross-sectional study, greater levels of fear, anxiety or isolation were associated with more aggressive breast cancer, consistent with a potential role for psychosocial stress in the etiology of breast cancer aggressiveness. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A91.

BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays

Purpose Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings. Methods We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software. Results BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001). Conclusion Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer.