Sanjay Shete

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (155)875.31 Total impact

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    ABSTRACT: Background: Smoking experimentation in Mexican American youth is problematic. In light of the research showing that preventing smoking experimentation is a valid strategy for smoking prevention, there is a need to identify Mexican American youth at high risk for experimentation. Methods: A prospective population-based cohort of 1179 adolescents of Mexican descent was followed for 5 years starting in 2005-06. Participants completed a baseline interview at a home visit followed by three telephone interviews at intervals of approximately 6 months and additional interviews at two home visits in 2008-09 and 2010-11. The primary end point of interest in this study was smoking experimentation. Information regarding social, cultural, and behavioral factors (e.g., acculturation, susceptibility to experimentation, home characteristics, household influences) was collected at baseline using validated questionnaires. Results: Age, sex, cognitive susceptibility, household smoking behavior, peer influence, neighborhood influence, acculturation, work characteristics, positive outcome expectations, family cohesion, degree of tension, ability to concentrate, and school discipline were found to be associated with smoking experimentation. In a validation dataset, the proposed risk prediction model had an AUC of 0.719 (95% confidence interval, 0.637 to 0.801) for predicting absolute risk for smoking experimentation within 1 year. Conclusions: The proposed risk prediction model is able to quantify the risk of smoking experimentation in Mexican American adolescents. Impact: Accurately identifying Mexican American adolescents who are at higher risk for smoking experimentation who can be intervened will substantially reduce the incidence of smoking and thereby subsequent health risks.
    07/2014;
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    ABSTRACT: Survival outcomes in patients with squamous cell carcinoma of the head and neck (HNSCC) vary by extent of disease, behavioral, and socioeconomic factors. We assessed the extent to which pre-treatment pain influences survival in 2340 newly diagnosed patients with HNSCC, adjusting for disease stage, symptoms, pain medications, comorbidities, smoking, alcohol consumption, age, sex, and race/ethnicity. Patients rated their pain at presentation to the cancer center (0= 'no pain' and 10= 'pain as bad as you can imagine'). Survival time was calculated from the date of diagnosis to the date of death of any cause or last follow-up. Five year overall survival was calculated for all the variables assessed in the study. Severe pain (>7) was most prevalent among those with oral cancer (20.4%; pharynx=18.8%; larynx=16.1%) and significantly varied by tumor stage, fatigue severity, smoking status, comorbid lung disease, and race (all p<0.05) across cancer diagnoses. Overall 5 year survival varied by pain for oral (severe pain=31% versus non-severe=52%; p<0.001) and pharyngeal cancer (severe pain=33%, versus non-severe=53%; p<0.001). Multivariable analyses showed that pain persisted as an independent prognostic factor for survival. Pain reported prior to treatment should be considered in understanding survival outcomes in HNSCC patients.
    The journal of pain : official journal of the American Pain Society. 07/2014;
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    ABSTRACT: Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
    Human Molecular Genetics 07/2014; · 7.69 Impact Factor
  • Jian Wang, Robert Yu, Sanjay Shete
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    ABSTRACT: X-chromosome inactivation (XCI) is the process in which one of the two copies of the X-chromosome in females is randomly inactivated to achieve the dosage compensation of X-linked genes between males and females. That is, 50% of the cells have one allele inactive and the other 50% of the cells have the other allele inactive. However, studies have shown that skewed or nonrandom XCI is a biological plausibility wherein more than 75% of cells have the same allele inactive. Also, some of the X-chromosome genes escape XCI, i.e., both alleles are active in all cells. Current statistical tests for X-chromosome association studies can either account for random XCI (e.g., Clayton's approach) or escape from XCI (e.g., PLINK software). Because the true XCI process is unknown and differs across different regions on the X-chromosome, we proposed a unified approach of maximizing likelihood ratio over all biological possibilities: random XCI, skewed XCI, and escape from XCI. A permutation-based procedure was developed to assess the significance of the approach. We conducted simulation studies to compare the performance of the proposed approach with Clayton's approach and PLINK regression. The results showed that the proposed approach has higher powers in the scenarios where XCI is skewed while losing some power in scenarios where XCI is random or XCI is escaped, with well-controlled type I errors. We also applied the approach to the X-chromosomal genetic association study of head and neck cancer.
    Genetic Epidemiology 07/2014; · 4.02 Impact Factor
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    Rajesh Talluri, Jian Wang, Sanjay Shete
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    ABSTRACT: Several methods have been proposed to account for multiple comparisons in genetic association studies. However, investigators typically test each of the SNPs using multiple genetic models. Association testing using the Cochran-Armitage test for trend assuming an additive, dominant, or recessive genetic model, is commonly performed. Thus, each SNP is tested three times. Some investigators report the smallest p-value obtained from the three tests corresponding to the three genetic models, but such an approach inherently leads to inflated type 1 errors. Because of the small number of tests (three) and high correlation (functional dependence) among these tests, the procedures available for accounting for multiple tests are either too conservative or fail to meet the underlying assumptions (e.g., asymptotic multivariate normality or independence among the tests).
    BMC genetics. 06/2014; 15(1):75.
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    ABSTRACT: The aim was to determine the proportions and correlates of essential hypertension among children in a tertiary pediatric hypertension clinic.
    American journal of hypertension. 05/2014;
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    ABSTRACT: IntroductionThe genetic heritability for sensation-seeking tendencies ranges from 40 to 60%. Sensation-seeking behaviors typically manifest during adolescence and are associated with alcohol and cigarette experimentation in adolescents. Social disinhibition is an aspect of sensation-seeking that is closely tied to cigarette and alcohol experimentation.Methods We examined the contribution of candidate genes to social disinhibition among 1132 Mexican origin youth in Houston, Texas, adjusting for established demographic and psychosocial risk factors. Saliva samples were obtained at baseline in 2005–06, and social disinhibition and other psychosocial data were obtained in 2008–09. Participants were genotyped for 672 functional and tagging SNPs potentially related to sensation-seeking, risk-taking, smoking, and alcohol use.ResultsSix SNPs were significantly associated with social disinhibition scores, after controlling for false discovery and adjusting for population stratification and relevant demographic/psychosocial characteristics. Minor alleles for three of the SNPs (rs1998220 on OPRM1; rs9534511 on HTR2A; and rs4938056 on HTR3B) were associated with increased risk of social disinhibition, while minor alleles for the other three SNPs (rs1003921 on KCNC1; rs16116 downstream of NPY; and rs16870286 on LINC00518) exhibited a protective effect. Age, linguistic acculturation, thrill and adventure-seeking, and drug and alcohol-seeking were all significantly positively associated with increased risk of social disinhibition in a multivariable model (P < 0.001).Conclusions These results add to our knowledge of genetic risk factors for social disinhibition. Additional research is needed to verify whether these SNPs are associated with social disinhibition among youth of different ethnicities and nationalities, and to elucidate whether and how these SNPs functionally contribute to social disinhibition.
    Brain and Behavior. 05/2014;
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    ABSTRACT: 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. 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. 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. 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.
    Neuro-Oncology 04/2014; · 6.18 Impact Factor
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    ABSTRACT: Because smoking has a profound impact on socioeconomic disparities in illness and death, it is crucial that vulnerable populations of smokers be targeted with treatment. The U.S. Public Health Service recommends that all patients be asked about their smoking at every visit and that smokers be given brief advice to quit and referred to treatment. Initiatives to facilitate these practices include the 5A's (ask, advise, assess, assist, arrange) and Ask-Advise-Refer (AAR). Unfortunately, primary care referrals are low, and most smokers referred fail to enroll. This study evaluated the efficacy of the Ask-Advise-Connect (AAC) approach to linking smokers with treatment in a large, safety net public healthcare system. The study design was a pair-matched group-randomized trial with two treatment arms. Ten safety net clinics in Houston TX. Clinics were randomized to AAC (n=5; intervention) or AAR (n=5; control). Licensed vocational nurses (LVNs) were trained to assess and record the smoking status of all patients at all visits in the electronic health record. Smokers were given brief advice to quit. In AAC, the names and phone numbers of smokers who agreed to be connected were sent electronically to the Texas quitline daily, and patients were proactively called by the quitline within 48 hours. In AAR, smokers were offered a quitline referral card and encouraged to call on their own. Data were collected between June 2010 and March 2012 and analyzed in 2012. The primary outcome was impact, defined here as the proportion of identified smokers that enrolled in treatment. The impact (proportion of identified smokers who enrolled in treatment) of AAC (14.7%) was significantly greater than the impact of AAR (0.5%), t(4)=14.61, p=0.0001, OR=32.10 (95% CI=16.60, 62.06). The AAC approach to aiding smoking cessation has tremendous potential to reduce tobacco-related health disparities. This study is registered at ISRCTN78799157.
    American journal of preventive medicine 12/2013; 45(6):737-41. · 4.24 Impact Factor
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    ABSTRACT: Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
    Genetic Epidemiology 11/2013; · 4.02 Impact Factor
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    ABSTRACT: We studied whether a melanoma survivor-centered intervention was more effective than materials available to the general public in increasing children's sun protection. In a randomized controlled trial, melanoma survivors (n = 340) who had a child ≤12 years received a targeted sun protection intervention (DVD and booklets) or standard education. Primary outcomes were children's sunburns, children's sun protection, and survivors' psychosocial factors at baseline and postintervention (1 and 4 months). The intervention increased children's sunscreen reapplication at 1 month (P = 0.002) and use of wide-brimmed hats at 4 months (P = 0.045). There were no effects on other behaviors or sunburns. The intervention improved survivors' hats/clothing self-efficacy at both follow-up assessments (P = 0.026, 0.009). At 4 months, the intervention improved survivors' clothing intentions (P = 0.029), knowledge (P = 0.010), and outcome expectations for hats (P = 0.002) and clothing (P = 0.037). Children's sun protection increased with survivors' intervention use. The intervention was less effective in survivors who were female or who had a family history, older children, or children with higher baseline sun protection scores. A melanoma survivor-centered sun protection intervention can improve some child and survivor outcomes. The intervention may be more effective in survivors who have younger children or less experience with sun protection. Intervention delivery must be enhanced to maximize use. This is the first study to examine a sun protection intervention for children of melanoma survivors. Findings will guide interventions for this important population at increased melanoma risk. Cancer Epidemiol Biomarkers Prev; 22(10); 1813-24. ©2013 AACR.
    Cancer Epidemiology Biomarkers &amp Prevention 10/2013; 22(10):1813-1824. · 4.56 Impact Factor
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    ABSTRACT: Symptom clusters, the multiple, co-occurring symptoms experienced by cancer patients, are debilitating and affects quality of life. We assessed if a panel of immune-response genes may underlie the co-occurrence of severe pain, depressed mood, and fatigue and help identify patients with severe versus non-severe symptom clusters. Symptoms were assessed at presentation, prior to cancer treatment in 599 newly diagnosed lung cancer patients. We applied cluster analyses to determine the patients with severe versus non-severe symptom clusters of pain, depressed mood, and fatigue. Two homogenous clusters were identified. One hundred sixteen patients (19 %) comprised the severe symptom cluster, reporting high intensity of pain, depressed mood, and fatigue and 183 (30 %) patients reported low intensity of these symptoms. Using Bayesian model averaging methodology, we found that of the 55 single nucleotide polymorphisms assessed, an additive effect of mutant alleles in endothelial nitric oxide synthase (-1474 T/A) (posterior probability of inclusion (PPI) = 0.78, odds ratio (OR) = 0.54, 95 % credible interval (CI) = (0.31, 0.93)); IL1B T-31C (PPI = 0.72, OR = 0.55, 95 % CI = (0.31, 0.97)); TNFR2 Met(196)Arg (PPI = 0.70, OR = 1.85, 95 % CI = (1.03, 3.36)); PTGS2 exon 10+837T > C (PPI = 0.69, OR = 0.54, 95 % CI = (0.28, 0.99)); and IL10RB Lys(47)Glu (PPI = 0.68; OR = 1.74; 95 % CI = (1.04, 2.92)) were predictive for symptom clusters. Genetic polymorphisms may facilitate identification of high-risk patients and development of individualized symptom therapies.
    Supportive Care in Cancer 07/2013; · 2.09 Impact Factor
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    ABSTRACT: Background:Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma.Methods:To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.Results:The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.Conclusion:Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.British Journal of Cancer advance online publication, 9 April 2013; doi:10.1038/bjc.2013.155 www.bjcancer.com.
    British Journal of Cancer 04/2013; · 5.08 Impact Factor
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    ABSTRACT: IMPORTANCE Several national health care-based smoking cessation initiatives have been recommended to facilitate the delivery of evidence-based treatments, such as quitline (telephone-based tobacco cessation services) assistance. The most notable examples are the 5 As (Ask, Advise, Assess, Assist, Arrange) and Ask. Advise. Refer. (AAR) programs. Unfortunately, rates of primary care referrals to quitlines are low, and most referred smokers fail to call for assistance. OBJECTIVE To evaluate a new approach-Ask-Advise-Connect (AAC)-designed to address barriers to linking smokers with treatment. DESIGN A pair-matched, 2-treatment-arm, group-randomized design in 10 family practice clinics in a single metropolitan area. Five clinics were randomized to the AAC (intervention) and 5 to the AAR (control) conditions. In both conditions, clinic staff were trained to assess and record the smoking status of all patients at all visits in the electronic health record, and smokers were given brief advice to quit. In the AAC clinics, the names and telephone numbers of smokers who agreed to be connected were sent electronically to the quitline daily, and patients were called proactively by the quitline within 48 hours. In the AAR clinics, smokers were offered a quitline referral card and encouraged to call on their own. All data were collected from February 8 through December 27, 2011. SETTING Ten clinics in Houston, Texas. PARTICIPANTS Smoking status assessments were completed for 42 277 patients; 2052 unique smokers were identified at AAC clinics, and 1611 smokers were identified at AAR clinics. INTERVENTIONS Linking smokers with quitline-delivered treatment. MAIN OUTCOME MEASURE Impact was based on the RE-AIM (Reach, Efficacy, Adoption, Implementation, and Maintenance) conceptual framework and defined as the proportion of all identified smokers who enrolled in treatment. RESULTS In the AAC clinics, 7.8% of all identified smokers enrolled in treatment vs 0.6% in the AAR clinics (t4 = 9.19 [P < .001]; odds ratio, 11.60 [95% CI, 5.53-24.32]), a 13-fold increase in the proportion of smokers enrolling in treatment. CONCLUSIONS AND RELEVANCE The system changes implemented in the AAC approach could be adopted broadly by other health care systems and have tremendous potential to reduce tobacco-related morbidity and mortality.
    JAMA Internal Medicine 02/2013; · 10.58 Impact Factor
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    ABSTRACT: We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
    Human Molecular Genetics 02/2013; · 7.69 Impact Factor
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    ABSTRACT: OBJECTIVES: To determine the difference in the risk factors for systemic hypertension in preterm and term infants in the neonatal intensive care unit (NICU). STUDY DESIGN: Data were collected from an existing database of NICU children and confirmed by chart review. Systemic hypertension was defined when 3 separate measurements of systolic and/or diastolic blood pressure were >95th percentile and an antihypertensive medication was administered for >2 weeks in the NICU. RESULTS: Of 4203 infants, we identified 53 (1.3%) with treated hypertension, of whom 74% were preterm, 11% required surgical intervention, and 85% required medications on discharge. The presence of a patent ductus arteriosus, umbilical catheterization, left ventricular hypertrophy, hypertensive medication at discharge, and mortality was similar between the term and preterm infants. The major risk factors for preterm infants, especially those <28 weeks' gestation, were bronchopulmonary dysplasia and iatrogenic factors, but, in term infants, they were systemic diseases. Term infants were diagnosed with hypertension earlier during hospitalization, had a shorter duration of stay in the NICU, and had a higher incidence of hypertension needing >3 medications than preterm infants. CONCLUSIONS: Perinatal risk factors are significant contributors to infantile hypertension. Term infants were diagnosed with hypertension earlier, had a shorter duration of stay, and had a higher incidence of resistant hypertension than preterm infants.
    The Journal of pediatrics 02/2013; · 4.02 Impact Factor
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    ABSTRACT: BACKGROUND: While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium. METHODS: Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires. FINDINGS: The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40y, and in 12% both were diagnosed under 40y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I-II were on average 17y younger than those with grades III-IV. INTERPRETATION: Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma.
    European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor
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    Rajesh Talluri, Sanjay Shete
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    ABSTRACT: Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant test statistics within a particular locus to improve power, and selecting a subset of rare variants for association testing, e.g., the step-up approach. We found that (a) if the variants being pooled are in linkage disequilibrium, the standard step-up method of selecting the best subset of variants results in loss of power compared to a model that pools all rare variants and (b) if the variants are in linkage equilibrium, performing a subset selection using step-based selection methods results in a gain of power of association compared to a model that pools all rare variants. Therefore, we propose an approach to selecting the best subset of variants to include in the model that is based on the linkage disequilibrium pattern among the rare variants. The proposed linkage disequilibrium-based variant selection model is flexible and borrows strength from the model that pools all rare variants when the rare variants are in linkage disequilibrium and from step-based selection methods when the variants are in linkage equilibrium. We performed simulations under three different realistic scenarios based on: (1) the HapMap3 dataset of the DRD2 gene, and CHRNA3/A5/B4 gene cluster (2) the block structure of linkage disequilibrium, and (3) linkage equilibrium. We proposed a permutation-based approach to control the type 1 error rate. The power comparisons after controlling the type 1 error show that the proposed linkage disequilibrium-based subset selection approach is an attractive alternative method for subset selection of rare variants.
    PLoS ONE 01/2013; 8(7):e69226. · 3.73 Impact Factor
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    ABSTRACT: A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.
    Frontiers in Psychiatry 01/2013; 4:114.
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    ABSTRACT: We, and others, have shown that experimenting with cigarettes is a function of both non-genetic and genetic factors. In this analysis we ask: how much of the total risk of experimenting with cigarettes, among those who had not experimented with cigarettes when they enrolled in a prospective cohort, is attributable to genetic factors and to non-genetic factors? Participants (N = 1,118 Mexican origin youth), recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Non-genetic data were elicited twice - baseline and follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways. In the overall model, the adjusted combined non-genetic PAF was 71.2% and the adjusted combined genetic PAF was 58.5%. Among committed never smokers the adjusted combined non-genetic PAF was 67.0% and the adjusted combined genetic PAF was 53.5%. However, among cognitively susceptible youth, the adjusted combined non-genetic PAF was 52.0% and the adjusted combined genetic PAF was 68.4%. Our results suggest there may be differences in genotypes between youth who think they will try cigarettes in the future compared to their peers who think they will not and underscore the possibility that the relative influence of genetic vs. non-genetic factors on the uptake of smoking may vary between these two groups of youth. A clearer understanding of the relative role of genetic vs. non-genetic factors in the uptake of smoking may have implications for the design of prevention programs.
    PLoS ONE 01/2013; 8(1):e53868. · 3.73 Impact Factor

Publication Stats

5k Citations
875.31 Total Impact Points

Institutions

  • 2002–2014
    • University of Texas MD Anderson Cancer Center
      • Department of Epidemiology
      Houston, Texas, United States
  • 2013
    • University of Texas at Austin
      Austin, Texas, United States
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2012
    • Baylor College of Medicine
      • Dan L. Duncan Cancer Center
      Houston, TX, United States
  • 2010–2011
    • Institute of Cancer Research
      • Division of Genetics and Epidemiology
      London, ENG, United Kingdom
  • 2005–2011
    • University of Texas Health Science Center at Houston
      • Department of Internal Medicine
      Houston, Texas, United States
  • 2006–2010
    • University of Texas Medical School
      • Department of Internal Medicine
      Houston, TX, United States
  • 2008
    • Washington University in St. Louis
      San Luis, Missouri, United States