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1.  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
2.  International Scientific Collaboration in HIV and HPV: A Network Analysis 
PLoS ONE  2014;9(3):e93376.
Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a “small-world phenomenon.” Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries.
doi:10.1371/journal.pone.0093376
PMCID: PMC3969316  PMID: 24682041
3.  Systematic Review and Meta-Analysis of L1-VLP-Based Human Papillomavirus Vaccine Efficacy against Anogenital Pre-Cancer in Women with Evidence of Prior HPV Exposure 
PLoS ONE  2014;9(3):e90348.
Background
It is unclear whether L1-VLP-based human papillomavirus (HPV) vaccines are efficacious in reducing the likelihood of anogenital pre-cancer in women with evidence of prior vaccine-type HPV exposure. This study aims to determine whether the combined results of the vaccine trials published to date provide evidence of efficacy compared with control (hepatitis A vaccine/placebo).
Methods
A systematic review and meta-analysis was conducted. Randomized-controlled trials (RCTs) were identified from MEDLINE, Embase, Web of Science, PubMed, Cochrane Central Register of Controlled Trials and references of identified studies. The bivalent vaccine containing HPV-16 and 18 VLPs from GlaxoSmithKline Biologicals (Rixenstart, Belgium), the quadrivalent vaccine containing HPV-6, 11, 16, and 18 VLPs from Merck & Co., Inc., (Whitehouse Station, NJ USA), and the HPV-16 monovalent vaccine from Merck Research Laboratories (West Point, PA USA) were evaluated.
Findings
Three RCT reports and two post-trial cohort studies were eligible, comprising data from 13,482 women who were included in the vaccine studies but had evidence of HPV infection at study entry. Data on efficacy was synthesized using the Mantel-Haenszel weighted fixed-effect approach, or where there was heterogeneity between studies, the DerSimonian and Laird weighted random-effect approach. The mean odds ratio (OR) and 95% confidence interval (CI) for the association between Cervarix, Gardasil and HPV-16 monovalent vaccine and HPV-associated cervical intraepithelial neoplasia grade 3 or worse was 0·90 (95% CI: 0·56, 1·44). For the association between Gardasil and HPV-associated vulval/vaginal intraepithelial neoplasia grades 2–3, the overall OR and 95% CI was 2.25 (95% CI: 0·78, 6.50). Sample size and follow-up were limited.
Conclusions
There was no evidence that HPV vaccines are effective in preventing vaccine-type HPV associated pre-cancer in women with evidence of prior HPV exposure. Small effects of vaccination however cannot be excluded and a longer-term benefit in preventing re-infection remains possible.
doi:10.1371/journal.pone.0090348
PMCID: PMC3940851  PMID: 24595046
4.  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
5.  MspI and Ile462Val Polymorphisms in CYP1A1 and Overall Cancer Risk: A Meta-Analysis 
PLoS ONE  2013;8(12):e85166.
Background
Cytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family, which is a key enzyme in the metabolism of many endogenous substrates and exogenous carcinogens. To date, many studies have examined the association between CYP1A1 MspI and Ile462Val polymorphisms and cancer risk in various populations, but their results have been conflicting rather than consistent.
Methods
To assess this relationship more precisely, a meta-analysis based on 198 publications was performed. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with a chi-square-based Q-test.
Results
Overall, a significant elevated risk of cancer was associated with CYP1A1 MspI and Ile462Val polymorphisms for all genetic models studied. Further stratified analysis by cancer types revealed that the MspI polymorphism may increase the risk of lung cancer and cervical cancer whereas the Ile462Val polymorphism may contribute to a higher risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer. In the subgroup analysis by ethnicity, obvious associations were found in the Asian population for the MspI polymorphism while an increased risk of cancer was observed in Asians and Caucasians for the Ile462Val polymorphism.
Conclusions
The results of this meta-analysis suggest that CYP1A1 MspI and Ile462Val polymorphisms contribute to increased cancer susceptibility among Asians. Additional comprehensive system analyses are required to validate this association and other related polymorphisms.
doi:10.1371/journal.pone.0085166
PMCID: PMC3877352  PMID: 24391993
6.  Second Cancers in Patients with Neuroendocrine Tumors 
PLoS ONE  2013;8(12):e86414.
Background
Second cancers have been reported to occur in 10-20% of patients with neuroendocrine tumors (NETs). However, most published studies used data from a single institution or focused only on specific sites of NETs. In addition, most of these studies included second cancers diagnosed concurrently with NETs, making it difficult to assess the temporality and determine the exact incidence of second cancers. In this nationwide population-based study, we used data recorded by the Taiwan Cancer Registry (TCR) to analyze the incidence and distribution of second cancers after the diagnosis of NETs.
Methods
NET cases diagnosed from January 1, 1996 to December 31, 2006 were identified from the TCR. The data on the occurrence of second cancers were ascertained up to December 31, 2008. Standardized incidence ratios (SIRs) of second cancers were calculated based on the cancer incidence rates of the general population. Cox-proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of second cancers associated with sex, age, and primary NET sites.
Results
A total of 1,350 newly diagnosed NET cases were identified according to the selection criteria. Among the 1,350 NET patients, 49 (3.63%) developed a second cancer >3 months after the diagnosis of NET. The risk of second cancer following NETs was increased compared to the general population (SIR = 1.48, 95% CI: 1.09-1.96), especially among those diagnosed at age 70 or older (HR = 5.08, 95% CI = 1.69-15.22). There appeared to be no preference of second cancer type according to the primary sites of NETs.
Conclusions
Our study showed that the risk of second cancer following NETs is increased, especially among those diagnosed at age 70 or older. Close monitoring for the occurrence of second cancers after the diagnosis of NETs is warranted.
doi:10.1371/journal.pone.0086414
PMCID: PMC3877400  PMID: 24392036
7.  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
8.  Famine in the Young and Risk of Later Hospitalization for COPD and Asthma 
PLoS ONE  2013;8(12):e82636.
Background
Undernutrition during critical periods of growth and development may permanently affect lung physiology and function.
Objectives
To investigate whether acute undernutrition in childhood or young adulthood increases the risk of later hospitalization for obstructive airways disease, chronic obstructive pulmonary disease (COPD), or asthma.
Methods
We studied 7,841 women from Prospect-EPIC who experienced the 1944–45 Dutch famine between ages 0 and 21. Pulmonary outcomes were measured by registered hospital admissions and exposure-blinded computed tomography (CT) in a subgroup of 295 women. With Cox proportional hazard regression we explored effects of famine exposure on risk of hospitalization for obstructive airways disease, COPD, and asthma. With logistic regression we explored effects of famine on risk of CT evidence of pulmonary disease.
Results
Risks of hospitalization for obstructive airways disease, COPD, and asthma were increased after moderate famine exposure, and significantly increased after severe famine exposure: hazard ratios for obstructive airways disease were 1.31 (95% CI: 0.97 to 1.77) and 1.57 (95% CI: 1.10 to 2.23) respectively. Associations between famine exposure and hospitalization for COPD were stronger in ever-smokers than in never-smokers.
Conclusions
Acute undernutrition in childhood or young adulthood is associated with an increased risk of later COPD and asthma hospitalization, possibly through increased sensitivity for tobacco smoke.
doi:10.1371/journal.pone.0082636
PMCID: PMC3871614  PMID: 24376558
9.  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
10.  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
11.  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
12.  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
13.  Family History as a Predictor for Disease Risk in Healthy Individuals: A Cross-Sectional Study in Slovenia 
PLoS ONE  2013;8(11):e80333.
Background
Family history can be used as a genetic risk predictor for common non-communicable diseases. The aim of this study was to determine the prevalence of healthy individuals at risk of developing these diseases, based on their self-reported family history.
Methods and Findings
This was a cross-sectional observational study. Data were collected in the three largest occupational practices in primary health care centres in Slovenia, a Central European country. The study population consisted of consecutive individuals who came to occupational practices for their regular preventive check-up from November 2010 to June 2012. We included 1,696 individuals. Data were collected by a self-developed questionnaire. The main outcome was the number of participants at a moderate or high risk for the development of cardiovascular diseases, diabetes, and cancer.
The final sample consisted of 1,340 respondents. Moderate or high risk for the development of cardiovascular diseases was present in 280 (20.9%) participants, for the development of diabetes in 154 (11.5%) participants and for cancer in 163 (12.1%) participants.
Conclusions
In this study, we found a significant proportion of healthy individuals with an increased genetic risk for common non-communicable diseases; consequently further genetic and clinical evaluation and preventive measures should be offered.
doi:10.1371/journal.pone.0080333
PMCID: PMC3819284  PMID: 24223224
14.  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
15.  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
16.  Association of X-ray Repair Cross Complementing Group 1 Arg399Gln Polymorphisms with the Risk of Squamous Cell Carcinoma of the Head and Neck: Evidence from an Updated Meta-Analysis 
PLoS ONE  2013;8(10):e77898.
Background
Epidemiologic studies have reported the association of X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln polymorphisms with susceptibility to squamous cell carcinoma of the head and neck (HNSCC). However, the results were conflictive rather than conclusive. The purpose of this study was to clarify the association of XRCC1 Arg399Gln variants with HNSCC risk.
Methods
Systematic searches were performed through the search engines of PubMed, Elsevier, Science Direct, CNKI and Chinese Biomedical Literature Database. Summary odds ratio (OR) with 95% confidence intervals (CI) was computed to estimate the strength association.
Results
Overall, we did not observe any association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in total population (OR = 0.95, 95% CI: 0.76–1.19 for Gln/Gln vs. Arg/Arg, OR = 1.05, 95% CI: 0.92–1.20 for Arg/Gln vs. Arg/Arg, and OR = 1.03, 95% CI: 0.90–1.18 for Gln/Gln+Arg/Gln vs. Arg/Arg) based on 18 studies including 3917 cases and 4560 controls. In subgroup analyses, we observed an increased risk of XRCC1 399 Arg/Gln genotype for HNSCC in Caucasians (OR = 1.20, 95% CI: 1.00–1.44) and Gln/Gln genotype for larynx squamous cell carcinoma (OR = 1.63, 95% CI: 1.10–2.40). We did not observe any association between XRCC1 Arg399Gln variants and HNSCC risk in additional subgroup analyses.
Conclusion
The results from this present meta-analysis suggest that XRCC1 Arg399Gln variants may contribute to HNSCC risk among Caucasians and to the risk of larynx squamous cell carcinoma. Further, well-designed studies with larger sample sizes are required to verify our findings.
doi:10.1371/journal.pone.0077898
PMCID: PMC3813759  PMID: 24205020
17.  GSTM1 and GSTT1 Null Polymorphisms and Childhood Acute Leukemia Risk: Evidence from 26 Case-Control Studies 
PLoS ONE  2013;8(10):e78810.
Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) null polymorphisms and childhood acute leukemia; however, the conclusions remain controversial. We performed an extensive meta-analysis on 26 published case-control studies with a total of 3252 cases and 5024 controls. Crude odds ratios (ORs) with 95% confidence interval were used to assess the strength of association between childhood acute leukemia risk and polymorphisms of GSTM1 and GSTT1. With respect to GSTM1 polymorphism, significantly increased risk of childhood acute leukemia was observed in the overall analysis (OR = 1.30; 95%CI, 1.11-1.51). Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism are associated with childhood acute leukemia in group of Asians (OR = 1.94; 95%CI, 1.53-2.46), Blacks (OR = 1.76; 95%CI, 1.07-2.91), ALL (OR = 1.33; 95%CI, 1.13-1.58), ‘< 100 cases and <100 controls’ (OR = 1.79; 95%CI, 1.21-2.64), ‘≥ 100 cases and ≥ 100 controls’ (OR = 1.25; 95%CI, 1.02-1.52), and population-based control source (OR = 1.40; 95%CI, 1.15-1.69). With respect to GSTT1 polymorphism, significant association with childhood acute leukemia risk was only found in subgroup of Asian. This meta-analysis supports that GSTM1 null polymorphism is capable of causing childhood acute leukemia susceptibility.
doi:10.1371/journal.pone.0078810
PMCID: PMC3806859  PMID: 24194954
18.  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
19.  Comparing the Performance of Hybrid Capture II and Polymerase Chain Reaction (PCR) for the Identification of Cervical Dysplasia in the Screening and Diagnostic Settings 
Objective
Both PCR and Hybrid Capture II (HCII) have been used for identifying cervical dysplasia; however, comparisons on the performance between these two tests show inconsistent results. We evaluated the performance of HCII and PCR MY09/11 in both screening and diagnostic populations in sub-sample of 1,675 non-pregnant women from a cohort in three clinical centers in the United States and Canada.
Methods
Sensitivity, specificity, positive predictive value, negative predictive value, and concordance between the two tests were calculated.
Results
Specificity of HCII in detecting low-grade squamous intraepithelial lesion (LSIL) was higher in the screening group (88.7%; 95% CI: 86.2%–90.8%) compared to the diagnostic group (46.3%; 95% CI: 42.1%–50.6%); however, specificity of PCR was low in both the screening (32.8%; 95% CI: 29.6%–36.2%) and diagnostic (14.4%; 95% CI: 11.6%–17.6%) groups. There was comparable sensitivity by both tests in both groups to detect high-grade squamous intraepithelial lesion (HSIL); however, HCII was more specific (89.1%; 95% CI: 86.8%–91.0%; 66.2%; 95% CI: 62.0%–70.1%) than PCR (33.3%; 95% CI: 30.2%–36.5%; 17.9%; 95% CI: 14.8%–21.6%) in the screening and diagnostic groups, respectively. Overall agreement for HPV positivity was approximately 50% between HCII and PCR MY09/11; with more positive results coming from the PCR MY09/11.
Conclusion
In the current study, PCR MY09/11 was more sensitive but less specific than HCII in detecting LSIL, and HCII was more sensitive and specific in detecting HSIL than PCR in both screening and diagnostic groups.
doi:10.4137/CMO.S12811
PMCID: PMC3795532  PMID: 24137052
comparison; test accuracy; hybrid capture II (HC II); polymerase chain reaction (PCR); cervical dysplasia
20.  Research Results: Preserving Newborn Blood Samples 
Science translational medicine  2012;4(159):159cm12.
doi:10.1126/scitranslmed.3004474
PMCID: PMC3763707  PMID: 23136040
21.  Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma 
Human genetics  2012;131(9):1507-1517.
Background
The risk of glioma has consistently been shown to be increased two-fold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23.
Methods
To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations.
Results
In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (Ptrend < 1.0 ×10−8).
Conclusion
The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.
doi:10.1007/s00439-012-1187-x
PMCID: PMC3604903  PMID: 22688887
Association; Polymorphisms; Glioma; Family history of primary brain tumor; Linkage analysis
22.  Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study 
Neuro-Oncology  2012;14(8):1018-1025.
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
doi:10.1093/neuonc/nos123
PMCID: PMC3408256  PMID: 22661588
Childhood Cancer Survivor Study; glutathione S-transferase polymorphisms; medulloblastoma; neuropsychological impairment; radiation therapy
23.  Predictors of Survival Among Pediatric and Adult Ependymoma Cases: A Study Using Surveillance, Epidemiology, and End Results Data from 1973–2007 
Neuroepidemiology  2012;39(2):116-124.
Background
Despite previous research, prognostic factors for ependymoma remain relatively controversial. The purpose of our study was to examine demographic, clinical, and tumor attributes as potential predictors of survival using Surveillance, Epidemiology, and End Results (SEER) program data (1973–2007).
Methods
All ependymoma (ICD-O-3 code 9391) and anaplastic ependymoma cases (ICD-O-3 code 9392) with complete data (n=2369 and n=319, respectively) were included from SEER. Predictive Cox regression models were built separately among pediatric and adult cases. Recursive partitioning was used to corroborate results from regression models.
Results
Among pediatric cases, tumor characteristics with a significantly increased mortality risk were anaplastic histology (vs. low grade, HR: 1.51, 95% CI: 1.04–2.19) and infratentorial tumor location (vs. spinal cord, HR: 3.86, 95% CI: 1.17–12.77). Among adults, supratentorial tumors were associated with higher mortality hazard (vs. spinal cord tumors) than infratentorial tumors (HR: 4.83, 95% CI: 3.49–6.68 & HR: 2.41, 95% CI: 1.79–3.25, respectively). Complete surgical resection of the tumor conferred the most protection among pediatric and adult patients.
Conclusion
Our results indicate that treatment type and tumor characteristics are important prognostic factors in patients with ependymoma. However, there may be key differences between pediatric and adult cases regarding how these factors influence survival.
doi:10.1159/000339320
PMCID: PMC3470871  PMID: 22846789
24.  Asthma Heredity, Cord Blood IgE and Asthma-Related Symptoms and Medication in Adulthood: A Long-Term Follow-Up in a Swedish Birth Cohort 
PLoS ONE  2013;8(6):e66777.
Cord blood IgE has previously been studied as a possible predictor of asthma and allergic diseases. Results from different studies have been contradictory, and most have focused on high-risk infants and early infancy. Few studies have followed their study population into adulthood. This study assessed whether cord blood IgE levels and a family history of asthma were associated with, and could predict, asthma medication and allergy-related respiratory symptoms in adults. A follow-up was carried out in a Swedish birth cohort comprising 1,701 consecutively born children. In all, 1,661 individuals could be linked to the Swedish Prescribed Drug Register and the Medical Birth Register, and 1,227 responded to a postal questionnaire. Cord blood IgE and family history of asthma were correlated with reported respiratory symptoms and dispensed asthma medication at 32–34 years. Elevated cord blood IgE was associated with a two- to threefold increased risk of pollen-induced respiratory symptoms and dispensed anti-inflammatory asthma medication. Similarly, a family history of asthma was associated with an increased risk of pollen-induced respiratory symptoms and anti-inflammatory medication. However, only 8% of the individuals with elevated cord blood IgE or a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication at follow-up. In all, 49 out of 60 individuals with dispensed anti-inflammatory asthma medication at 32–34 years of age had not been reported having asthma at previous check-ups of the cohort during childhood. Among those, only 5% with elevated cord blood IgE and 6% with a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication as adults. Elevated cord blood IgE and a positive family history of asthma were associated with reported respiratory symptoms and dispensed asthma medication in adulthood, but their predictive power was poor in this long-time follow-up.
doi:10.1371/journal.pone.0066777
PMCID: PMC3689672  PMID: 23805276
25.  Comparison of the accuracy of Hybrid Capture II and polymerase chain reaction in detecting clinically important cervical dysplasia: a systematic review and meta-analysis 
Cancer Medicine  2013;2(3):367-390.
The effectiveness of screening programs for cervical cancer has benefited from the inclusion of Human papillomavirus (HPV) DNA assays; which assay to choose, however, is not clear based on previous reviews. Our review addressed test accuracy of Hybrid Capture II (HCII) and polymerase chain reaction (PCR) assays based on studies with stronger designs and with more clinically relevant outcomes. We searched OvidMedline, PubMed, and the Cochrane Library for English language studies comparing both tests, published 1985–2012, with cervical dysplasia defined by the Bethesda classification. Meta-analysis provided pooled sensitivity, specificity, and 95% confidence intervals (CIs); meta-regression identified sources of heterogeneity. From 29 reports, we found that the pooled sensitivity and specificity to detect high-grade squamous intraepithelial lesion (HSIL) was higher for HCII than PCR (0.89 [CI: 0.89–0.90] and 0.85 [CI: 0.84–0.86] vs. 0.73 [CI: 0.73–0.74] and 0.62 [CI: 0.62–0.64]). Both assays had higher accuracy to detect cervical dysplasia in Europe than in Asia-Pacific or North America (diagnostic odd ratio – dOR = 4.08 [CI: 1.39–11.91] and 4.56 [CI: 1.86–11.17] for HCII vs. 2.66 [CI: 1.16–6.53] and 3.78 [CI: 1.50–9.51] for PCR) and accuracy to detect HSIL than atypical squamous cells of undetermined significance (ASCUS)/ low-grade squamous intraepithelial lesion (LSIL) (HCII-dOR = 9.04 [CI: 4.12–19.86] and PCR-dOR = 5.60 [CI: 2.87–10.94]). For HCII, using histology as a gold standard results in higher accuracy than using cytology (dOR = 2.87 [CI: 1.31–6.29]). Based on higher test accuracy, our results support the use of HCII in cervical cancer screening programs. The role of HPV type distribution should be explored to determine the worldwide comparability of HPV test accuracy.
doi:10.1002/cam4.83
PMCID: PMC3699849  PMID: 23930214
Human papillomavirus; hybrid capture II; meta-analysis; polymerase chain reaction; test accuracy

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