Steven A Belinsky

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

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Publications (211)1394.72 Total impact

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    ABSTRACT: Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology seen in former uranium miners. Radon exposure can cause oxidative stress leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development. Objectives: We assessed whether single nucleotide polymorphisms (SNP) in the IL-6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas. Methods: Genetic associations were assessed in a case control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the GENEVA Genome Wide Association Study of Lung Cancer and Smoking study. Functional relevance of the SNPs was characterized using in vitro approaches. Results: Rs1800797 was associated with squamous cell carcinoma in miners, and with a shorter time between midpoint of the period of substantial exposure and diagnosis among the cases. Rs1800797 also was associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo(a)pyrene diolepoxide treatments. Conclusions: An IL-6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that IL-6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion. .
    Environmental Health Perspectives 09/2015; DOI:10.1289/ehp.1409437 · 7.98 Impact Factor
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    ABSTRACT: Lung cancer and chronic obstructive pulmonary disease (COPD) share environmental risk factors. COPD also increases the risk of lung cancer; however, the molecular mechanisms are unclear. An epigenome-wide association study of lung tumors and cancer-free lung tissue (CFLT) pairs from non-small-cell lung cancer cases with (n = 18) or without (n = 17) COPD was conducted using the HumanMethylation450 beadchip (HM450K). COPD-associated methylation of top-ranked genes was confirmed in a larger sample set, independently validated, and their potential as sputum-based biomarkers was investigated. Methylation of CCDC37 and MAP1B was more prevalent in lung tumors from COPD than non-COPD cases [54 of 71 (76%) versus 20 of 46 (43%), p = 0.0013] and [48 of 71 (68%) versus 17 of 46 (37%), p = 0.0035], respectively, after adjustment for age, sex, smoking status, and tumor histology. HM450K probes across CCDC37 and MAP1B promoters showed higher methylation in tumors than CFLT with the highest methylation seen in tumors from COPD cases (p < 0.05). These results were independently validated using The Cancer Genome Atlas data. CCDC37 methylation was more prevalent in sputum from COPD than non-COPD smokers (p < 0.005) from two cohorts. CCDC37 and MAP1B expression was dramatically repressed in tumors and CFLT from COPD than non-COPD cases, p less than 0.02. The reduced expression of CCDC37 and MAP1B associated with COPD likely predisposes these genes to methylation that in turn, may contribute to lung cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2015; 10(8):1181-8. DOI:10.1097/JTO.0000000000000592 · 5.28 Impact Factor
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    ABSTRACT: O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single-nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells, while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells. Cancer Res; 75(15); 1-10. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Research 07/2015; 75(15). DOI:10.1158/0008-5472.CAN-15-0243 · 9.33 Impact Factor
  • European Respiratory Journal 07/2015; DOI:10.1183/13993003.00682-2015 · 7.64 Impact Factor
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    ABSTRACT: Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. Methods: A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. Results: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. Conclusions: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.
    JNCI Journal of the National Cancer Institute 02/2015; 107(5). DOI:10.1093/jnci/djv035 · 12.58 Impact Factor
  • Steven A Belinsky
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    ABSTRACT: The reprogramming of the epigenome through silencing of genes and microRNAs by cytosine DNA methylation and chromatin remodeling is critical for the initiation and progression of lung cancer through affecting all major cell regulatory pathways. Importantly, the fact that epigenetic reprogramming is reversible by pharmacological agents has opened new avenues for clinical intervention. This review focuses on the tremendous progress made in elucidating genes and microRNAs that are epigenetically silenced in lung cancer and highlights how loss of function impacts cell phenotype and major signaling pathways. The article describes the utility of (a) an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines to identify genes and microRNAs silenced during premalignancy and (b) an in vivo orthotopic nude rat lung cancer model to evaluate response to epigenetic therapy. New insights regarding the advantage of aerosol delivery of demethylating agents and the concept of priming tumors for subsequent therapy are presented and discussed.
    Annual Review of Physiology 02/2015; 77(1):453-74. DOI:10.1146/annurev-physiol-021014-072018 · 18.51 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3554-3554. DOI:10.1158/1538-7445.AM2014-3554 · 9.33 Impact Factor
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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; 17(2). DOI:10.1177/1099800414538113 · 1.43 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; 9(6). DOI:10.1097/JTO.0000000000000165 · 5.28 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; 7(3). DOI:10.1016/j.tranon.2014.03.001 · 2.88 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; 21(7). DOI:10.1038/cdd.2014.25 · 8.18 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; 20(7). DOI:10.1158/1078-0432.CCR-13-2109 · 8.72 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; 34(5). DOI:10.1038/onc.2013.580 · 8.46 Impact Factor
  • S. A. Belinsky · A. Spira · C. Tellez
    Cancer Prevention Research 01/2014; 5(11_Supplement):CN06-02-CN06-02. DOI:10.1158/1940-6207.PREV-12-CN06-02 · 4.44 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. DOI:10.1186/1465-9921-15-2 · 3.09 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; 35(6). DOI:10.1093/carcin/bgt494 · 5.33 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; 74(2). DOI:10.1158/0008-5472.CAN-13-1713 · 9.33 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; 110(47). DOI:10.1073/pnas.1220319110 · 9.67 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 09/2013; 109(7). DOI:10.1038/bjc.2013.575 · 4.84 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; 188(9). DOI:10.1164/rccm.201305-0925OC · 13.00 Impact Factor

Publication Stats

9k Citations
1,394.72 Total Impact Points


  • 1993–2015
    • Lovelace Respiratory Research Institute
      • Respiratory Immunology and Asthma Program
      Albuquerque, New Mexico, United States
  • 2012
    • University of New Mexico
      Albuquerque, New Mexico, United States
  • 2010
    • University of New Mexico Hospitals
      Albuquerque, New Mexico, United States
  • 2006
    • Shinshu University
      • Department of Surgery
      Shonai, Nagano, Japan
  • 2004
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2002
    • University of Texas MD Anderson Cancer Center
      • Department of Thoracic Head Neck Medical Oncology
      Houston, TX, United States
  • 1996
    • University of Dundee
      Dundee, Scotland, United Kingdom
    • Johns Hopkins University
      • Department of Surgery
      Baltimore, Maryland, United States
  • 1994–1995
    • Albuquerque Academy
      Albuquerque, New Mexico, United States
  • 1987–1993
    • National Institute of Environmental Health Sciences
      • Cellular & Molecular Pathology Branch
      Durham, North Carolina, United States
  • 1980–1991
    • University of North Carolina at Chapel Hill
      • Department of Pharmacology
      North Carolina, United States
  • 1988
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States