Steven A Belinsky

Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States

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Publications (168)1040.16 Total impact

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    ABSTRACT: Gene methylation is an epigenetic change that involves a heritable modification of chromatin structure that alters gene expression without a change in DNA sequence. It has previously been shown that methylation of the GATA-4 gene promoter region in sputum DNA is associated with low lung function and increased odds of chronic obstructive pulmonary disease (COPD) among smokers. Given these findings, we hypothesized that GATA-4 gene methylation in sputum DNA would be associated with low health status, as measured by the St. George's Respiratory Questionnaire (SGRQ), in subjects with COPD. Self-reported SGRQ, spirometry, and induced sputum samples were obtained from 168 COPD subjects from the Lovelace Smokers Cohort. GATA-4 gene methylation was evaluated in sputum DNA using nested methylation-specific polymerase chain reaction (PCR) assays. Using general linear model with Poisson regression, we found that GATA-4 gene methylation was significantly associated with overall lower SGRQ health status (parameter estimate = .296, p < .001). This finding remained significant even after controlling for age, lung function, and other covariates. In an additional analysis using logistic regression and comparing extreme tertiles of overall SGRQ score, we confirmed that GATA-4 gene methylation was associated with a 3-fold increase in risk of poor health status (OR 2.95 and p = .028). The unexplored links between epigenetic changes and psychosocial factors such as health status are critical gaps in the literature. This study is the first to suggest that airway GATA-4 gene methylation status may independently predict health status in individuals with COPD.
    Biological Research for Nursing 06/2014; · 1.85 Impact Factor
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    ABSTRACT: GATA2 was recently described as a critical survival factor and therapeutic target for KRAS mutant non-small-cell lung cancer (NSCLC). However, whether this role is affected by epigenetic repression of GATA2 in lung cancer is unclear. GATA2 expression and promoter CpG island methylation were evaluated using human and mouse NSCLC cell lines and tumor-normal pairs. In vitro assays were used to study GATA2 repression on cell survival and during tobacco carcinogen-induced transformation. GATA2 expression in KRAS wild-type (n = 15) and mutant (n = 10) NSCLC cell lines and primary lung tumors (n = 24) was significantly lower, 1.3- to 33.6-fold (p = 2.2 × 10), compared with corresponding normal lung. GATA2 promoter was unmethylated in normal lung (0 of 10) but frequently methylated in lung tumors (96%, 159 of 165) and NSCLC cell lines (97%, 30 of 31). This highly prevalent aberrant methylation was independently validated using The Cancer Genome Atlas data for 369 NSCLC tumor-normal pairs. In vitro studies using an established carcinogen-induced premalignancy model revealed that GATA2 expression was initially repressed by chromatin remodeling followed by cytosine methylation during transformation. Similarly, expression of GATA2 in NNK-induced mouse lung tumors (n = 6) and cell lines (n = 5) was fivefold and 100-fold lower, respectively, than normal mouse lung. Finally, siRNA-mediated knockdown of GATA2 in KRAS mutant (human [n = 4] and murine [n = 5]) and wild-type (human [n = 4]) NSCLC cell lines showed that further reduction of expression (up to 95%) does not induce cell death. GATA2 is epigenetically repressed in human and mouse lung tumors and its further inhibition is not a valid therapeutic strategy for KRAS mutant lung cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2014; · 4.55 Impact Factor
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    ABSTRACT: Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.
    Translational oncology 04/2014; · 3.40 Impact Factor
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    ABSTRACT: The DNA methyltransferase (DNMT) inhibitor vidaza (5-Azacytidine) in combination with the HDAC inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI-110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat. Evaluation of in vivo plasma concentrations and pharmacokinetic properties of SGI-110 showed rapid conversion to decitabine and a plasma half-life of 4 hours. SGI-110 alone or in combination with entinostat reduced tumor burden of a K-ras/p53 mutant lung adenocarcinoma cell line (Calu6) engrafted orthotopically in nude rats by 35% and 56%, respectively. SGI-110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with SGI-110 alone or in combination with entinostat. Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy. In the orthotopically growing tumors, highly significant gene expression changes were seen in key cancer regulatory pathways including induction of p21 and the apoptotic gene BIK. Moreover, SGI-110 in combination with entinostat caused widespread epigenetic reprogramming of EZH2-target genes. These preclinical in vivo findings demonstrate the clinical potential of SGI-110 for reducing lung tumor burden through reprogramming the epigenome. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; · 6.20 Impact Factor
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    ABSTRACT: Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.Cell Death and Differentiation advance online publication, 28 February 2014; doi:10.1038/cdd.2014.25.
    Cell death and differentiation 02/2014; · 8.24 Impact Factor
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    ABSTRACT: Purpose: Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer. Following previously validated methods for the discovery of cancer-specific hypermethylation changes we treated 8 NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publically available database and two independent cohorts of primary samples. We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and employing extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This 3-gene panel is 100% specific, showing no methylation in 75 TCGA normal and 7 primary normal samples and is 83-99% sensitive for NSCLC depending on the cohort. This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this 3-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC.
    Clinical Cancer Research 01/2014; · 7.84 Impact Factor
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    ABSTRACT: The maintenance cytosine DNA methyltransferase DNMT1 and de novo methyltransferase DNMT3b cooperate to establish aberrant DNA methylation and chromatin complexes to repress gene transcription during cancer development. The expression of DNMT3b was constitutively increased 5-20-fold in hTERT/CDK4-immortalized human bronchial epithelial cells (HBECs) before treatment with low doses of tobacco carcinogens. Overexpression of DNMT3b increased and accelerated carcinogen-induced transformation. Genome-wide profiling of transformed HBECs identified 143 DNMT3b-target genes, many of which were transcriptionally regulated by the polycomb repressive complex 2 (PRC2) complex and silenced through aberrant methylation in non-small-cell lung cancer cell lines. Two genes studied in detail, MAL and OLIG2, were silenced during transformation, initially through enrichment for H3K27me3 and H3K9me2, commonly methylated in lung cancer, and exert tumor suppressor effects in vivo through modulating cancer-related pathways. Re-expression of MAL and OLIG2 to physiological levels dramatically reduced the growth of lung tumor xenografts. Our results identify a key role for DNMT3b in the earliest stages of initiation and provide a comprehensive catalog of genes targeted for silencing by this methyltransferase in non-small-cell lung cancer.Oncogene advance online publication, 27 January 2014; doi:10.1038/onc.2013.580.
    Oncogene 01/2014; · 8.56 Impact Factor
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    ABSTRACT: Chronic mucous hypersecretion (CMH) contributes to COPD exacerbations and increased risk for lung cancer. Because methylation of gene promoters in sputum has been shown to be associated with lung cancer risk, we tested whether such methylation was more common in persons with CMH. Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used to profile the sputum of 900 individuals in the Lovelace Smokers Cohort (LSC). Replication was performed in 490 individuals from the Pittsburgh Lung Screening Study (PLuSS). CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the LSC and PLuSS (OR = 2.72, 95 % CI = 1.51-4.91, p = 0.001 and OR = 2.97, 95 % CI = 1.48-5.95, p = 0.002, respectively). Further, the association between methylation and CMH was more pronounced among 139 male former smokers with persistent CMH compared to current smokers (SULF2; OR = 3.65, 95 % CI = 1.59-8.37, p = 0.002). These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.
    Respiratory research 01/2014; 15(1):2. · 3.64 Impact Factor
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    ABSTRACT: Lung cancer in never smokers (NS) shows striking demographic, clinico-pathological, and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n=3) and NS (n=3) each treated with vehicle (control), histone deacetylation inhibitor (TSA), or DNA methylation inhibitor (DAC). Among 122 genes re-expressed following DAC but not TSA treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer (NSCLC) cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in NSCLC (≤10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n=97) and NS (n=75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN, and MARVELD3 (p<0.05). Furthermore, methylation of EMILIN2, ROBO3, and IGDCC4 was more prevalent in advanced (Stage II-IV, n=61) than early (Stage I, n=110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by siRNA significantly reduced anchorage-independent growth of lung cancer cells (p < 0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.
    Carcinogenesis 01/2014; · 5.64 Impact Factor
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    ABSTRACT: Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke (CS) increases Muc1 expression in lung macrophages, where we hypothesized it might contribute to CS-induced transformation of bronchial epithelial cells. In human macrophages, CS extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced ERK activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNAi-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α processing enzyme TACE, arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE inducion through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells (HBEC) in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK and MUC1 that is used by CSE to trigger TNF-α secretion from macrophages. Further, our results show how that MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals driven by macrophages.
    Cancer Research 11/2013; · 9.28 Impact Factor
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    ABSTRACT: Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Although microRNAs are regulators of many airway gene-expression changes induced by smoking, their role in modulating changes associated with lung cancer in these cells remains unknown. Here, we use next-generation sequencing of small RNAs in the airway to identify microRNA 4423 (miR-4423) as a primate-specific microRNA associated with lung cancer and expressed primarily in mucociliary epithelium. The endogenous expression of miR-4423 increases as bronchial epithelial cells undergo differentiation into mucociliary epithelium in vitro, and its overexpression during this process causes an increase in the number of ciliated cells. Furthermore, expression of miR-4423 is reduced in most lung tumors and in cytologically normal epithelium of the mainstem bronchus of smokers with lung cancer. In addition, ectopic expression of miR-4423 in a subset of lung cancer cell lines reduces their anchorage-independent growth and significantly decreases the size of the tumors formed in a mouse xenograft model. Consistent with these phenotypes, overexpression of miR-4423 induces a differentiated-like pattern of airway epithelium gene expression and reverses the expression of many genes that are altered in lung cancer. Together, our results indicate that miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis.
    Proceedings of the National Academy of Sciences 10/2013; · 9.81 Impact Factor
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    ABSTRACT: Background:Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised.Methods:The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared.Results:Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug.Conclusion:Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.British Journal of Cancer advance online publication, 17 September 2013; doi:10.1038/bjc.2013.575
    British Journal of Cancer 09/2013; · 5.08 Impact Factor
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    ABSTRACT: Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic Whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer. Objectives: This study compared the methylation prevalence in sputum of NHWs to Hispanics using the Lovelace Smokers cohort (n=1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk. Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific PCR. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between packyears and risk for lung cancer was assessed in the New Mexico lung cancer study. Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (OR = 1.18, P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non-small cell lung cancer cases have significantly lower packyears than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of packyears (P = 0.058). Conclusions: NAA may be important risk modifiers for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
    American Journal of Respiratory and Critical Care Medicine 09/2013; · 11.04 Impact Factor
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    ABSTRACT: Cigarette smoking is the most important risk factor for chronic obstructive pulmonary disease (COPD) in the United States. Host factors that influence rapid rate of FEV1 decline in smokers and how decline rate influences risk for developing COPD are unknown. Characterize the rate of FEV1 decline in ever-smokers, compare the risk of incident COPD between rapid decliners and others, and determine the effect of selected drugs on rapid decline. A total of 1,170 eligible ever-smokers from the longitudinal Lovelace Smokers Cohort with repeat spirometry tests over a minimum follow-up period of 3 years (mean follow-up: 5.9 years) were examined, including 809 ever-smokers without baseline spirometric abnormality. Longitudinal absolute decline in postbronchodilator FEV1 obtained from the slope defined by the spirometric values over all examinations was annualized and classified as 'rapid' (≥30 ml/year), 'normal' (0 to -29.9 ml/year) or 'no' decline (>0 ml/year). Logistic regression and Kaplan-Meir survival curves were used for analysis. Approximately 32% of ever-smokers exhibited rapid decline. Among ever-smokers without baseline spirometric abnormality, rapid decline was associated with increased risk for incident COPD [OR 1.88; p = 0.003]. The use of angiotensin converting enzyme (ACE) inhibitor at baseline examination was protective against rapid decline, particularly among those with co-morbid cardiovascular disease, hypertension, or diabetes [OR 0.48; 0.48 and 0.12 respectively; p≤ 0.02 for all analyses]. Ever-smokers with rapid decline in FEV1 are at higher risk for developing COPD. Use of ACE inhibitors by smokers may protect against 'rapid' decline and progression to COPD.
    Chest 09/2013; · 7.13 Impact Factor
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    ABSTRACT: Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non-small-cell lung cancer (NSCLC) receiving selenium supplementation. Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence. The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected. Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC.
    Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
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    ABSTRACT: PURPOSE: Gene promoter hypermethylation may have utility as a biomarker for cancer risk in histopathologically benign prostate specimens. MATERIALS AND METHODS: We conducted a nested case-control study of gene promoter methylation status for five genes (APC, RARB, CCND2, RASSF1, MGMT), measured in benign biopsy specimens from 511 prostate cancer case-control pairs. We estimated the overall and race-stratified risk of subsequent prostate cancer associated with methylation status. RESULTS: In race-stratified analyses, RARB methylation was associated with higher cancer risk in African Americans (OR=2.18; CI=1.39-3.44). APC methylation was associated with increased risk for high-grade tumors (OR=2.43; CI=1.20-4.90); this risk was higher in African Americans than Whites (OR=3.21 vs. 2.04). In cases, methylation of the RARB and APC genes in benign prostate persisted in matched malignant specimens; in African American cases, combined risk associated with methylation of RARB and APC (OR=3.04; CI=1.44-6.42) was greater than the individual risk of each gene and significantly different from that observed in Whites (OR=1.14; CI=0.56-2.30). CONCLUSION: We conclude that methylation of the RARB gene in histopathologically benign prostate is associated with statistically significant increased risk for subsequent prostate cancer in African American men. Methylation data on additional genes may improve risk stratification and clinical decision-making algorithms for cancer screening and diagnosis.
    The Journal of urology 01/2013; · 3.75 Impact Factor
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    ABSTRACT: Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks (DSBs) induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P=0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (Odds Ratio = 1.69, P = 8.2×10(-5)) and greater survival in SCC cases (Hazard Ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggested that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
    Carcinogenesis 01/2013; · 5.64 Impact Factor
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    ABSTRACT: The estimation of genetic ancestry in human populations has important applications in medical genetic studies. Genetic ancestry is used to control for population stratification in genetic association studies, and is used to understand the genetic basis for ethnic differences in disease susceptibility. In this review, we present an overview of genetic ancestry estimation in human disease studies, followed by a review of popular softwares and methods used for this estimation.
    Human genomics 01/2013; 7(1):1.
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    ABSTRACT: Low-dose ionizing radiation (LDR) may lead to suppression of smoking-related lung cancer. We examined the effects of a known cigarette smoke carcinogen Benzo[a]pyrene (B[a]P) alone or in combination with fractionated low-dose gamma radiation (60 - 600 mGy total dose) on the induction of lung neoplasms in the A/J mouse. Our results show that 600 mGy of gamma radiation delivered in six biweekly fractions of 100 mGy starting 1 month after B[a]P injection significantly inhibits the development of lung adenomas per animal induced by B[a]P. Our data also indicated that the six biweekly doses suppressed the occurrence of spontaneous hyperplastic foci in the lung, although this suppression failed to reach statistical significance when analyzed as average foci per lung possibly related to the small sample sizes used for the control and test groups.
    Dose-Response 12/2012; 10(4):516-26. · 1.50 Impact Factor
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    BMC proceedings 10/2012; 6(6).

Publication Stats

7k Citations
1,040.16 Total Impact Points


  • 1993–2014
    • Lovelace Respiratory Research Institute
      • Respiratory Immunology and Asthma Program
      Albuquerque, New Mexico, United States
  • 1998–2012
    • University of New Mexico
      • • School of Medicine
      • • Department of Internal Medicine
      Albuquerque, NM, United States
  • 2010
    • University of New Mexico Hospitals
      Albuquerque, New Mexico, United States
  • 2008
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2004
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2003
    • National Cancer Institute (USA)
      • Cell and Cancer Biology Branch
      Maryland, United States
  • 2002
    • University of Southern California
      • Norris Comprehensive Cancer Center
      Los Angeles, CA, United States
  • 2001
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 1996
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1987–1993
    • National Institute of Environmental Health Sciences
      Durham, North Carolina, United States