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1.  Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group 
Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex, and age. The following atopic conditions were assessed: allergies, asthma, eczema, and hives; in addition we examined other immune-related factors: birth order, day-care attendance, and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income, and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41–0.87), hives (OR=0.61, 95% CI: 0.38–0.97), day-care attendance (OR=0.48, 95% CI: 0.32–0.71), and breastfeeding for ≥12 months (OR=0.36, 95% CI: 0.18–0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system’s role in the development of this tumor.
doi:10.1002/ijc.28363
PMCID: PMC3869863  PMID: 23824786
Allergies; atopy; epidemiology; rhabdomyosarcoma; soft tissue sarcoma
2.  A Pooled Multisite Analysis of the Effects of Female Reproductive Hormones on Glioma Risk 
Cancer causes & control : CCC  2014;25(8):1007-1013.
Purpose
The association between female reproductive factors and glioma risk is unclear, but most published studies have been limited by small sample size. We conducted a pooled multisite study of pre- and post-menopausal women, investigating the effect of female reproductive factors, including hormonal medications.
Methods
Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals assessing the effects of female reproductive factors and female hormonal medications in glioma cases and unrelated controls.
Results
Menarche over the age of 15 as compared to under 12 was associated with a statistically significant risk for glioma (OR = 2.00, 95% CI, 1.47–2.71). Use of Oral Contraceptive Pills (OCP) was inversely associated with risk of glioma (OR= 0.61, 95% CI, 0.50–0.74) and there was an inverse trend with longer duration of OCP use (p for trend< 0.0001). Use of Hormone Replacement Therapy (HRT) was also inversely associated with risk of glioma (OR=0.55, 95% CI, 0.44–0.68) and there was an inverse trend with longer duration of use (p for trend< 0.0001). Compared to those reporting neither OCP use nor HRT use, those who reported using both were less likely to have a diagnosis of glioma (OR = 0.34, 95% CI, 0.24–0.48).
Conclusions
Female reproductive hormones may decrease the risk for glioma. The association appears to be strongest with greater length of use and use of both HRT and OCP.
doi:10.1007/s10552-014-0400-8
PMCID: PMC4288736  PMID: 24890803
HRT; Hormones; Females; Contraceptives; Glioma
3.  Brain Tumor Epidemiology – A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014  
Clinical Neuropathology  2014;34(1):40-46.
The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 – 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue-based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year’s meeting, which will be held at the Mayo Clinic at Rochester, MN, USA.
doi:10.5414/NP300846
PMCID: PMC4317580  PMID: 25518914
brain tumor; epidemiology; clinical research; tissue-based research; risk factor research
4.  Antihistamine Use and Immunoglobulin E Levels in Glioma Risk and Prognosis 
Cancer epidemiology  2013;37(6):10.1016/j.canep.2013.08.004.
Objective
An inverse association between personal history of allergies/asthma and glioma risk has been fairly consistently reported in the epidemiologic literature. However, the role of regular antihistamine use remains controversial due to a small number of studies reporting contradictory findings. We evaluated the association between regular use of oral antihistamines and glioma risk, adjusting for a number of relevant factors (e.g., immunoglobulin E levels and history of chickenpox).
Methods
We used a subset of the Harris County Case-Control Study, which included 362 pathologically-confirmed glioma cases and 462 cancer-free controls, to evaluate this association using unconditional multivariable logistic regression. These models were run among the overall study population and stratified by allergy status. Cox regression was utilized to examine whether antihistamine use was associated with mortality among all cases and separately among high-grade cases.
Results
Antihistamine use was strongly associated with glioma risk among those with a positive allergy/asthma history (OR: 4.19, 95% CI: 2.06–8.51), but not among those with a negative history (OR: 1.59, 95% CI: 0.95–2.67). There were no significant associations between antihistamine use and survival among cases.
Conclusion
The current study implies that regular antihistamine use may increase glioma risk. However, several larger studies are necessary before definitive conclusions can be drawn.
doi:10.1016/j.canep.2013.08.004
PMCID: PMC3851921  PMID: 23994286
brain neoplasms; risk factors; epidemiology; survival; case-control studies; hypersensitivity; immunoglobulin E
5.  Age patterns of Kaposi's sarcoma incidence in a cohort of HIV-infected men 
Cancer Medicine  2014;3(6):1635-1643.
The life expectancy for HIV-positive individuals has improved over time due to increasing access to highly active antiretroviral therapy (HAART). Yet, as the HIV-positive population ages, their risk of developing cancers also increases. Studies of Kaposi's sarcoma (KS) among elderly HIV-infected persons are quite limited. We examined the age patterns of KS incidence and an association between age and KS risk in a US cohort of 3458 HIV-infected men, the Multicenter AIDS Cohort Study (MACS). Poisson distribution was used to calculate incidence rates and respective 95% confidence intervals (95% CIs). Cox proportional hazards regression was performed to examine the association between age and KS risk. There were 534 incident KS cases with a total follow-up time of 25,134 person-years. The overall KS incidence rate was 2.13 per 100 person-years (95% CI: 1.95–2.32) (Non-HAART users-ever: 5.57 per 100 person-years [95% CI: 5.09–6.10]; HAART users-ever: 0.39 per 100 person-years [95% CI: 0.31–0.51]). Overall, KS frequency and incidence declined with age, even in the oldest age group (ptrend < 0.0001). However, among non-HAART users-ever, the oldest age group had the highest incidence rate ratio compared to younger individuals [15.01, 95% CI: 6.12–44.22]). While the incidence of KS decreased with age, older HIV-infected persons who do not receive HAART are still at increased risk of KS. As KS remains an important malignancy among HIV-infected persons, earlier HIV diagnoses and HAART initiation, particularly in older HIV-infected persons is warranted.
doi:10.1002/cam4.312
PMCID: PMC4298390  PMID: 25139791
HIV-infected men; incidence patterns by age; Kaposi's sarcoma
6.  Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: An analysis of Surveillance, Epidemiology, and End Results data 
Cancer causes & control : CCC  2013;24(11):1985-1994.
Purpose
While cervical cancer screening and risk behaviors have been found to vary among U.S.- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity.
Methods
We use data from the Surveillance, Epidemiology, and End Results (SEER) program, 1998–2008. Nativity was based on place of birth and was categorized as U.S.- versus foreign-born. Distant and regional tumors were classified as late-stage, while local tumors were classified as early-stage.
Results
Forty seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than U.S.-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration= 1.09, p-value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus U.S.-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy (adjusted HR = 1.31, p-value = 0.030). However, among cases with late-stage diagnosis, survival was better among foreign--born Hispanics (adjusted HR = 0.81, p-value < 0.001).
Conclusions
We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research.
doi:10.1007/s10552-013-0274-1
PMCID: PMC4115245  PMID: 23934001
Cervical cancer; Hispanic; SEER program; survival; stage at diagnosis; nativity
7.  Evaluation of HPV Infection and Smoking Status Impacts on Cell Proliferation in Epithelial Layers of Cervical Neoplasia 
PLoS ONE  2014;9(9):e107088.
Accurate cervical intra-epithelial neoplasia (CIN) lesion grading is needed for effective patient management. We applied computer-assisted scanning and analytic approaches to immuno-stained CIN lesion sections to more accurately delineate disease states and decipher cell proliferation impacts from HPV and smoking within individual epithelial layers. A patient cohort undergoing cervical screening was identified (n = 196) and biopsies of varying disease grades and with intact basement membranes and epithelial layers were obtained (n = 261). Specimens were sectioned, stained (Mib1), and scanned using a high-resolution imaging system. We achieved semi-automated delineation of proliferation status and epithelial cell layers using Otsu segmentation, manual image review, Voronoi tessellation, and immuno-staining. Data were interrogated against known status for HPV infection, smoking, and disease grade. We observed increased cell proliferation and decreased epithelial thickness with increased disease grade (when analyzing the epithelium at full thickness). Analysis within individual cell layers showed a ≥50% increase in cell proliferation for CIN2 vs. CIN1 lesions in higher epithelial layers (with minimal differences seen in basal/parabasal layers). Higher rates of proliferation for HPV-positive vs. -negative cases were seen in epithelial layers beyond the basal/parabasal layers in normal and CIN1 tissues. Comparing smokers vs. non-smokers, we observed increased cell proliferation in parabasal (low and high grade lesions) and basal layers (high grade only). In sum, we report CIN grade-specific differences in cell proliferation within individual epithelial layers. We also show HPV and smoking impacts on cell layer-specific proliferation. Our findings yield insight into CIN progression biology and demonstrate that rigorous, semi-automated imaging of histopathological specimens may be applied to improve disease grading accuracy.
doi:10.1371/journal.pone.0107088
PMCID: PMC4161429  PMID: 25210770
8.  Nativity differences in behaviors associated with high-risk HPV infection among Hispanic women in Houston, Texas, USA 
While Hispanics in the U.S. are a population with significant within-group heterogeneity, epidemiologic studies often aggregate Hispanics into one homogenous group without considering differences by nativity. The objective of this study is to evaluate nativity differences in the risk behavior profile associated with prevalent high risk human papillomavirus (HR-HPV) among U.S.- and foreign-born Hispanic women. Using a clinical trial dataset, we compare risk behavior and HR-HPV infection patterns among U.S.- and foreign-born participants and assess factors associated with infection in each group. While the prevalence of HR-HPV infection was similar among U.S.- and foreign-born participants, U.S.-born cases had a higher HR-HPV risk profile. The similar prevalence of HR-HPV despite foreign-born women's lower risk profile suggests a role for unmeasured risk factors among foreign-born Hispanics. More importantly, nativity differences in behavioral risk factors associated with HR-HPV suggest the need to further research cervical cancer risk factors among disaggregated Hispanic subgroups.
doi:10.1007/s10903-012-9770-8
PMCID: PMC3675190  PMID: 23300005
Human Papillomavirus; risk behaviors; sexual behaviors; Hispanics; nativity
10.  Association of traffic-related hazardous air pollutants and cervical dysplasia in an urban multiethnic population: a cross-sectional study 
Environmental Health  2014;13:52.
Background
Human papillomavirus (HPV) infection is a necessary cause in the development of cervical cancer; however, not all women infected with HPV develop cervical cancer indicating that other risk factors are involved. Our objective was to determine the association between exposure to ambient levels of common traffic-related air toxics and cervical dysplasia, a precursor lesion for cervical cancer.
Methods
The study sample consisted of women enrolled in a Phase II clinical trial to evaluate diagnostic techniques for cervical disease in Houston, Texas. The current assessment is a secondary data analysis in which cases were defined as women diagnosed with cervical dysplasia, while those without cervical dysplasia served as controls. Residential census tract-level estimates of ambient benzene, diesel particulate matter (DPM), and polycyclic aromatic hydrocarbons (PAHs) were used to assess exposure. Census tract-level pollutant estimates were obtained from the United States Environmental Protection Agency. Multivariable logistic regression was used to estimate prevalence odds ratios (aOR) and 95% confidence intervals (CI) adjusted for age, race/ethnicity, education, smoking status, and HPV status.
Results
Women in the highest residential exposure categories for benzene and DPM had an increased prevalence of cervical dysplasia compared to the lowest exposure category (Benzene: aOR [95% CI] for high exposure = 1.97[1.07-3.62], very high exposure = 2.30[1.19-4.46]. DPM: aOR [95% CI] for high exposure = 2.83[1.55-5.16], very high exposure = 2.10[1.07-4.11]). Similarly, women with high residential exposure to PAHs had an increased prevalence of cervical dysplasia (aOR [95% CI] = 2.46[1.35-4.48]). The highest PAH exposure category was also positively associated with cervical dysplasia prevalence but was not statistically significant. Assessment of the combined effect of HAP exposure indicates that exposure to high levels of more than one HAP is positively associated with cervical dysplasia prevalence (p for trend = 0.004).
Conclusions
Traffic-related HAPs, such as benzene, DPM, and PAHs, are not as well-regulated and monitored as criteria air pollutants (e.g., ozone), underscoring the need for studies evaluating the role of these toxicants on disease risk. Our results suggest that exposure to traffic-related air toxics may increase cervical dysplasia prevalence.
doi:10.1186/1476-069X-13-52
PMCID: PMC4063240  PMID: 24924773
Benzene; Cervical dysplasia; Diesel particulate matter; Hazardous air pollutants; Polycyclic aromatic hydrocarbons
11.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Background
Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions.
Objectives
The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies.
Methods
By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens.
Conclusions
CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.
doi:10.1016/j.canep.2012.12.011
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
12.  Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia 
Leukemia research  2013;37(5):531-535.
Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology.
doi:10.1016/j.leukres.2013.01.020
PMCID: PMC3622777  PMID: 23433810
Acute lymphoblastic leukemia; case-parent triad; haplotypes; xenobiotic metabolism
13.  Integration of epidemiology, immunobiology, and translational research for brain tumors 
We recently identified a pivotal role for the host type I interferon (IFN) pathway in immuno-surveillance against de novo mouse glioma development, especially through the regulation of immature myeloid cells (IMCs) in the glioma microenvironment. Using these data, we identified single nucleotide polymorphisms (SNPs) in human IFN genes that dictate altered prognosis of patients with glioma. One of these SNPs (rs12553612) is located in the promoter of IFNA8, whose promoter activity is influenced by rs12553612. Conversely, recent epidemiologic data show that chronic usage of non-steroidal anti-inflammatory drugs lowers the risk of glioma. We translated these findings back to our de novo glioma model and found that cyclooxygenase-2 inhibition enhances anti-glioma immuno-surveillance by reducing glioma-associated IMCs. Taken together, these findings suggest that alterations in myeloid cell function condition the brain for glioma development. Finally, we have begun applying novel immunotherapeutic approaches to patients with low-grade glioma with the aim of preventing malignant transformation. Future research will hopefully better integrate epidemiological, immunobiological, and translational techniques to develop novel preventive approaches for malignant gliomas.
doi:10.1111/nyas.12115
PMCID: PMC3648859  PMID: 23651189
interferon; glioma; non-steroidal anti-inflammatory drugs; single nucleotide polymorphism
14.  Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer 
Andersson, Ulrika | Wibom, Carl | Cederquist, Kristina | Aradottir, Steina | Borg, Åke | Armstrong, Georgina N. | Shete, Sanjay | Lau, Ching C. | Bainbridge, Matthew N. | Claus, Elizabeth B. | Barnholtz-Sloan, Jill | Lai, Rose | Il'yasova, Dora | Houlston, Richard S. | Schildkraut, Joellen | Bernstein, Jonine L. | Olson, Sara H. | Jenkins, Robert B. | Lachance, Daniel H. | Wrensch, Margaret | Davis, Faith G. | Merrell, Ryan | Johansen, Christoffer | Sadetzki, Siegal | Bondy, Melissa L. | Melin, Beatrice S. | Adatto, Phyllis | Morice, Fabian | Payen, Sam | McQuinn, Lacey | McGaha, Rebecca | Guerra, Sandra | Paith, Leslie | Roth, Katherine | Zeng, Dong | Zhang, Hui | Yung, Alfred | Aldape, Kenneth | Gilbert, Mark | Weinberger, Jeffrey | Colman, Howard | Conrad, Charles | de Groot, John | Forman, Arthur | Groves, Morris | Levin, Victor | Loghin, Monica | Puduvalli, Vinay | Sawaya, Raymond | Heimberger, Amy | Lang, Frederick | Levine, Nicholas | Tolentino, Lori | Saunders, Kate | Thach, Thu-Trang | Iacono, Donna Dello | Sloan, Andrew | Gerson, Stanton | Selman, Warren | Bambakidis, Nicholas | Hart, David | Miller, Jonathan | Hoffer, Alan | Cohen, Mark | Rogers, Lisa | Nock, Charles J | Wolinsky, Yingli | Devine, Karen | Fulop, Jordonna | Barrett, Wendi | Shimmel, Kristen | Ostrom, Quinn | Barnett, Gene | Rosenfeld, Steven | Vogelbaum, Michael | Weil, Robert | Ahluwalia, Manmeet | Peereboom, David | Staugaitis, Susan | Schilero, Cathy | Brewer, Cathy | Smolenski, Kathy | McGraw, Mary | Naska, Theresa | Rosenfeld, Steven | Ram, Zvi | Blumenthal, Deborah T. | Bokstein, Felix | Umansky, Felix | Zaaroor, Menashe | Cohen, Avi | Tzuk-Shina, Tzeela | Voldby, Bo | Laursen, René | Andersen, Claus | Brennum, Jannick | Henriksen, Matilde Bille | Marzouk, Maya | Davis, Mary Elizabeth | Boland, Eamon | Smith, Marcel | Eze, Ogechukwu | Way, Mahalia | Lada, Pat | Miedzianowski, Nancy | Frechette, Michelle | Paleologos, Nina | Byström, Gudrun | Svedberg, Eva | Huggert, Sara | Kimdal, Mikael | Sandström, Monica | Brännström, Nikolina | Hayat, Amina | Tihan, Tarik | Zheng, Shichun | Berger, Mitchel | Butowski, Nicholas | Chang, Susan | Clarke, Jennifer | Prados, Michael | Rice, Terri | Sison, Jeannette | Kivett, Valerie | Duo, Xiaoqin | Hansen, Helen | Hsuang, George | Lamela, Rosito | Ramos, Christian | Patoka, Joe | Wagenman, Katherine | Zhou, Mi | Klein, Adam | McGee, Nora | Pfefferle, Jon | Wilson, Callie | Morris, Pagan | Hughes, Mary | Britt-Williams, Marlin | Foft, Jessica | Madsen, Julia | Polony, Csaba | McCarthy, Bridget | Zahora, Candice | Villano, John | Engelhard, Herbert | Borg, Ake | Chanock, Stephen K | Collins, Peter | Elston, Robert | Kleihues, Paul | Kruchko, Carol | Petersen, Gloria | Plon, Sharon | Thompson, Patricia | Johansen, C. | Sadetzki, S. | Melin, B. | Bondy, Melissa L. | Lau, Ching C. | Scheurer, Michael E. | Armstrong, Georgina N. | Liu, Yanhong | Shete, Sanjay | Yu, Robert K. | Aldape, Kenneth D. | Gilbert, Mark R. | Weinberg, Jeffrey | Houlston, Richard S. | Hosking, Fay J. | Robertson, Lindsay | Papaemmanuil, Elli | Claus, Elizabeth B. | Claus, Elizabeth B. | Barnholtz-Sloan, Jill | Sloan, Andrew E. | Barnett, Gene | Devine, Karen | Wolinsky, Yingli | Lai, Rose | McKean-Cowdin, Roberta | Il'yasova, Dora | Schildkraut, Joellen | Sadetzki, Siegal | Yechezkel, Galit Hirsh | Bruchim, Revital Bar-Sade | Aslanov, Lili | Sadetzki, Siegal | Johansen, Christoffer | Kosteljanetz, Michael | Broholm, Helle | Bernstein, Jonine L. | Olson, Sara H. | Schubert, Erica | DeAngelis, Lisa | Jenkins, Robert B. | Yang, Ping | Rynearson, Amanda | Andersson, Ulrika | Wibom, Carl | Henriksson, Roger | Melin, Beatrice S. | Cederquist, Kristina | Aradottir, Steina | Borg, Åke | Merrell, Ryan | Lada, Patricia | Wrensch, Margaret | Wiencke, John | Wiemels, Joe | McCoy, Lucie | McCarthy, Bridget J. | Davis, Faith G.
Neuro-Oncology  2014;16(10):1333-1340.
Background
Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers.
Methods
Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma.
Results
We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer.
Conclusions
Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
doi:10.1093/neuonc/nou052
PMCID: PMC4165415  PMID: 24723567
CDKN2A/B; family history; glioma; MLH1; MSH2; TP53
15.  Glutathione S-Transferase P1 Single Nucleotide Polymorphism Predicts Permanent Ototoxicity in Children with Medulloblastoma 
Pediatric blood & cancer  2012;60(4):593-598.
Background
Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A>G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events.
Procedure
The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons.
Results
Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥ 34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95%CI 1.2-13.6, and OR 3.1, 95%CI 1.1-8.8, respectively, n=69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4-49.9, p-trend=0.005, n=69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained.
Conclusions
The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.
doi:10.1002/pbc.24366
PMCID: PMC3549321  PMID: 23065688
Glutathione S-Transferase; Polymorphism; Radiation; Ototoxicity; Medulloblastoma
16.  Sociodemographic Factors Associated with Pap Test Adherence and Cervical Dysplasia in Surgically Sterilized Women 
Background
Routine dysplasia screening decreases the rates of cervical cancer. Since many women seek gynecological care to secure contraception, it was hypothesized that sterilized women will be less likely to undergo routine cervical cancer screening. Prior studies tried to evaluate this relationship, but results were conflicting. The study sought to further explore the sociodemographic and behavioral risk factors that might predispose sterilized women to be screening non-adherent and more likely to have cervical dysplasia.
Methods
Secondary analysis of women (n=1688) enrolled in a cross-sectional study in North America and divided into screening (n=925) and diagnostic (n=763) groups was performed. Information about sociodemographic and behavioral risk factors, surgical sterilization and date of last Pap test were obtained from questionnaires. Cervical histology was obtained from pathology records. Univariable analyses identified differences in risk factors between groups. Multivariable logistic regression models were constructed to evaluate Pap adherence and cervical dysplasia.
Results
Sterilized women were 39% more likely to be screening non-adherent (p≤0.05) especially if divorced, separated or widowed (OR=1.62), Hispanic (OR=1.57) and with a higher number of vaginal births (OR=2.00). Education was an effect measure modifier, significantly associated with non-adherence (OR=1.60). The association between sterilization and non-adherence remained significant when adjusted for confounders (AOR=1.47). Sterilization was associated with an 80% increased odds of cervical dysplasia in women over 40.
Conclusion
Sterilized women with certain sociodemographic factors are more likely to be non-adherent with Pap screening and more prone to dysplasia. These findings may assist practitioners in counseling at-risk patients.
PMCID: PMC4032975  PMID: 24918082
Cervical dysplasia screening; Pap test cervical dysplasia; Sterilization; Tubal ligation
17.  A Novel Approach to Exploring Potential Interactions among Single-Nucleotide Polymorphisms of Inflammation Genes in Gliomagenesis: An Exploratory Case-Only Study 
Background
Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNPs) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies.
Methods
The study population consisted of two case groups: 1224 histological-confirmed, non-Hispanic white glioma cases from the U.S. and a validation population of 634 glioma cases from the U.K. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the odds ratios of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes.
Results
Using this data-mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations.
Conclusion
This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk.
Impact
This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology.
doi:10.1158/1055-9965.EPI-11-0203
PMCID: PMC3904785  PMID: 21724854
18.  Epidemiologic differentiation of diagnostic and screening populations for the assessment of cervical dysplasia using optical technologies 
Gender medicine  2012;9(1 0):10.1016/j.genm.2011.10.006.
Background
We report here the logistic modeling of the epidemiologic differences between a diagnostic and screening population recruited for the study of optical technologies for cervical cancer detection.
Methods
Epidemiologic data were obtained from a risk factor interview as a component of a multicenter Phase II clinical trial which employed fluorescence and reflectance point spectroscopy to diagnose cervical disease. Participants with a recent or past abnormal Papanicolaou smear were grouped into the diagnostic (high-risk) population, while those with a history of normal Papanicolaou smears and no cervical treatments were grouped into the screening (low-risk) population.
Results
Our model revealed that non-white race, greater than a high school education, and peri- and postmenopausal status were associated with the screening population. Meanwhile, a history of genital infections, current OC use, HPV positivity (by Hybrid Capture II and consensus PCR), and histology at clinic visit were important predictors of being in the diagnostic group.
Conclusions
We were successful in recruiting two distinctive populations, and we anticipate being able to use these results to more correctly classify women at higher risk for cervical lesions in our future studies of optical spectroscopy.
doi:10.1016/j.genm.2011.10.006
PMCID: PMC3874883  PMID: 22340639
cervical dysplasia; epidemiology; optical technologies; risk factors
19.  Using a Bayesian Hierarchical Model for Identifying Single Nucleotide Polymorphisms Associated with Childhood Acute Lymphoblastic Leukemia Risk in Case-Parent Triads 
PLoS ONE  2013;8(12):e84658.
Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children’s Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.
doi:10.1371/journal.pone.0084658
PMCID: PMC3868670  PMID: 24367687
20.  Predictors of Survival Among Older Adults with Ependymoma 
Journal of neuro-oncology  2011;107(1):10.1007/s11060-011-0730-2.
Purpose
The biological process of aging encompasses a multitude of complex physiological and lifestyle changes that may alter the way typical prognostic factors affect survival among older ependymoma patients. Because very little is known about the clinical significance of traditional prognostic factors and the magnitude of their effects among older individuals, the purpose of this study was to evaluate the associations between survival and demographic and tumor characteristics among patients with ependymoma who were 60 years of age or older.
Methods
Using the 1973–2007 dataset from the Surveillance, Epidemiology and End Results (SEER) program, we evaluated the impact of several factors on both overall and ependymoma-specific survival, utilizing multivariable Cox proportional hazards regression.
Results
We identified 367 ependymoma cases who were 60 years of age or older at diagnosis and had complete data from SEER. Of these, 19 (5.2%) had anaplastic tumors; all others were low-grade tumors. Age, tumor site, extent of surgery, and tumor histology were found to be significant predictors of ependymoma prognosis. The strongest predictor of poor outcome was supratentoral tumor location (adjusted HR: 6.94, 95% CI: 3.19–15.08, compared to spinal cord tumors).
Conclusion
Our study suggests that tumor location, tumor histology, and surgical margin may be key predictors of survival among older ependymoma patients. We believe our study is one of the first to assess the prognostic value of these factors for ependymoma survival exclusively in an older patient population.
doi:10.1007/s11060-011-0730-2
PMCID: PMC3863332  PMID: 21952907
21.  Maternal Variation in EPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study 
Pediatric hematology and oncology  2012;29(8):10.3109/08880018.2012.722747.
Common epidemiologic study designs used for evaluating germline genetic determinants of childhood medulloblastoma are often subject to population stratification bias and do not account for maternal genetic effects, a proxy for the intrauterine environment, which may be important in determining etiologic factors for this outcome. The case-parent triad design overcomes these limitations. Therefore, we conducted an exploratory study among 27 childhood medulloblastoma case-parent triads recruited from the Childhood Cancer Epidemiology and Prevention Center at Texas Children’s Hospital (Houston, TX) between 2003 and 2010. We assessed 13 single nucleotide polymorphisms (SNPs) in nine xenobiotic detoxification genes, as deficiencies in this pathway may induce brain tumorigenesis. Log-linear modeling was used to assess the association between medulloblastoma and both the offspring (i.e., case) and maternal genotypes of each SNP. In our population, there were no offspring genotypes that were significantly associated with disease risk. However, the maternal EPHX1 rs1051740 genotype (RR=3.26, P=0.01) was associated with medulloblastoma risk. This exploratory study highlights the utility of the case-parent triad design, but these results should be interpreted cautiously due to the limited sample size.
doi:10.3109/08880018.2012.722747
PMCID: PMC3855527  PMID: 22994552
Case-parent triad; epidemiology; genetic polymorphisms; medulloblastoma; xenobiotic detoxification
22.  Clinical Implications of the Cervical Papanicolaou Test Results in the Management of Anal Warts in HIV-Infected Women 
PLoS ONE  2013;8(11):e81751.
The Papanicolaou test (or Pap test) has long been used as a screening tool to detect cervical precancerous/cancerous lesions. However, studies on the use of this test to predict both the presence and change in size of genital warts are limited. We examined whether cervical Papanicolaou test results are associated with the size of the largest anal wart over time in HIV-infected women in an on-going cohort study in the US. A sample of 976 HIV-infected women included in a public dataset obtained from the Women’s Interagency HIV Study (WIHS) was selected for analysis. A linear mixed model was performed to determine the relationship between the size of anal warts and cervical Pap test results. About 32% of participants had abnormal cervical Pap test results at baseline. In the adjusted model, a woman with a result of Atypia Squamous Cell Undetermined Significance/Low-grade Squamous Intraepithelial Lesion (ASCUS/LSIL) had an anal wart, on average, 12.81 mm2 larger than a woman with normal cervical cytology. The growth rate of the largest anal wart after each visit in a woman with ASCUS/LSIL was 1.56 mm2 slower than that of a woman with normal cervical results. However, they were not significant (P = 0.54 and P = 0.82, respectively). This is the first study to examine the relationship between cervical Pap test results and anal wart development in HIV-infected women. Even though no association between the size of anal wart and cervical Pap test results was found, a screening program using anal cytology testing in HIV-infected women should be considered. Further studies in cost-effectiveness and efficacy of an anal cytology test screening program are warranted.
doi:10.1371/journal.pone.0081751
PMCID: PMC3842937  PMID: 24312348
23.  Potential role of gastrointestinal microbiota composition in prostate cancer risk 
Background
Among men in the U.S., prostate cancer is the most common cancer and the second leading cause of cancer death. Despite its prevalence, there are few established risk factors for prostate cancer. Some studies have found that intake of certain foods/nutrients may be associated with prostate cancer risk, but few have accounted for how intake and metabolic factors may interact to influence bioavailable nutrient levels and subsequent disease risk.
Presentation of the hypothesis
The composition of the gastrointestinal (GI) microbiome may influence metabolism of dietary compounds and nutrients (e.g., plant phenols, calcium, choline) that may be relevant to prostate cancer risk. We, therefore, propose the hypothesis that GI microbiota may have a markedly different composition among individuals with higher prostate cancer risk. These individuals could have microbial profiles that are conducive to intestinal inflammation and/or are less favorable for the metabolism and uptake of chemopreventive agents.
Testing the hypothesis
Because very little preliminary data exist on this potential association, a case–control study may provide valuable information on this topic. Such a study could evaluate whether the GI microbial profile is markedly different between three groups of individuals: healthy men, those with latent prostate cancer, and those with invasive prostate cancer. Any findings could then be validated in a larger study, designed to collect a series of specimens over time.
Implications of the hypothesis
Given the plethora of information emerging from the Human Microbiome Project, this is an opportune time to explore associations between the microbiome and complex human diseases. Identification of profiles that alter the host’s risk for disease may clarify inconsistencies in the literature on dietary factors and cancer risk, and could provide valuable targets for novel cancer prevention strategies.
doi:10.1186/1750-9378-8-42
PMCID: PMC3826836  PMID: 24180596
Human microbiome; Metagenome; Prostate cancer; Metabolic process
24.  A case-parent triad assessment of folate metabolic genes and the risk of childhood acute lymphoblastic leukemia 
Cancer causes & control : CCC  2012;23(11):1797-1803.
Purpose
We conducted a case-parent triad study evaluating the role of maternal and offspring genotypes in the folate metabolic pathway on childhood acute lymphoblastic leukemia (ALL) risk.
Methods
Childhood ALL case-parent triads (N = 120) were recruited from Texas Children’s Hospital. DNA samples were genotyped using the Sequenom iPLEX MassARRAY for 68 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between maternal and offspring genotypes and ALL.
Results
After controlling for the false discovery rate (<0.1), there were 20 significant maternal effects in the following genes: BHMT (N = 3), MTR (N = 12), and TYMS (N = 5). For instance, maternal genotypes for BHMT rs558133 (relative risk [RR] = 0.51, 95% confidence interval [CI]: 0.30–0.87, P = 0.008, Q = 0.08) and MTR rs2282369 (RR = 0.46, 95% CI: 0.27–0.80, P = 0.004, Q = 0.08) were associated with ALL. There were no significant offspring effects after controlling for the false discovery rate.
Conclusions
This is one of the few studies conducted to evaluate maternal genetic effects in the context of childhood ALL risk. Furthermore, we employed a family-based design that is less susceptible to population stratification bias in the estimation of maternal genetic effects. Our findings suggest that maternal genetic variation in the folate metabolic pathway is relevant in the etiology of childhood ALL. The observed maternal genetic effects support the need for continued research of how the uterine environment may influence risk of ALL.
doi:10.1007/s10552-012-0058-z
PMCID: PMC3472623  PMID: 22941668
Acute lymphoblastic leukemia; case-parent triad; folate; genetic epidemiology; pediatric cancer
25.  An Exploratory Case-Only Analysis of Gene-Hazardous Air Pollutant Interactions and the Risk of Childhood Medulloblastoma 
Pediatric blood & cancer  2012;59(4):605-610.
Background
There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants, however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk.
Procedure
We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children’s Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the U.S. EPA’s 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs).
Results
There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04).
Conclusions
This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.
doi:10.1002/pbc.24105
PMCID: PMC3371277  PMID: 22389292
Hazardous air pollutants; chlorinated solvents; DNA repair genes; detoxification genes; childhood medulloblastoma and primitive neuroectodermal tumor

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