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Gene-Expression Signatures of Nasal Polyps Associated with Chronic Gene-expression signatures of nasal polyps associated with chronic rhinosinusitis and aspirin-sensitive asthma Michael Platta, Ralph Metsonb and Konstantina Stankovicb,c,d aDepartment of Otolaryngology, Head and Neck Purpose of review Surgery, Boston University, bDepartment of Otology and Laryngology, Harvard Medical School, The purpose of this review is to highlight recent advances in gene-expression profiling of cDepartment of Otolaryngology and dEaton Peabody nasal polyps in patients with chronic rhinosinusitis and aspirin-sensitive asthma. Laboratory, Massachusetts Eye and Ear Infirmary, Recent findings Boston, Massachusetts, USA Gene-expression profiling has allowed simultaneous interrogation of thousands of genes, Correspondence to Konstantina Stankovic, MD, PhD, Massachusetts Eye and Ear Infirmary, 243 Charles St., including the entire genome, to better understand distinct biological and clinical Boston, MA 02114, USA phenotypes associated with nasal polyps. The genes with altered expression in nasal Tel: +1 617 523 7900; e-mail: [email protected] polyps are involved in many cellular processes, including growth and development, immune functions, and signal transduction. The wide-ranging and typically Current Opinion in Allergy and Clinical Immunology 2009, 9:23–28 nonoverlapping results reported in the published studies reflect methodological and demographic differences. The identified genes present possible novel therapeutic targets for nasal polyps associated with chronic rhinosinusitis and aspirin-sensitive asthma. Summary Gene-expression profiling is a powerful technology that allows definition of expression signatures to characterize patient subgroups, predict response to treatment, and offer novel therapies. Although the ability to interpret the meaning of the individual gene in these signatures remains a challenge, integrated analysis of a large number of these signatures with other genome-scale data sets and more traditional targeted approaches has a potential to revolutionarize understanding and treatment of chronic rhinosinusitis and aspirin-sensitive asthma. Keywords aspirin-sensitive asthma, chronic rhinosinusitis, expression signatures, gene- expression profiling, microarray, nasal polyps Curr Opin Allergy Clin Immunol 9:23–28 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1528-4050 glass slide called a microarray. The microarray technology Introduction has revolutionized the field of genetic analysis, making it Sinusitis is one of the most commonly diagnosed and possible to define patterns of gene expression, that is, economically taxing diseases in the United States [1–3]. expression signatures, which are unique to a given bio- Patients with chronic rhinosinusitis (CRS) who are most logical state. The power of expression signatures is two- refractory to treatment develop sinonasal polyps. A sub- fold: the enormous complexity of the expression data set of these patients has aspirin-sensitive asthma (ASA, provides the opportunity to identify patterns of expres- i.e. triad asthma or Samter’s triad) distinguished by the sion that reflect different and novel phenotypic sub- presence of nasal polyps, asthma, and aspirin allergy. groups with distinct biology and expression signatures Sinonasal polyps are histologically characterized by can be assayed in varied contexts, including human tissue numerous changes in the mucosal epithelium and under- and experimentally manipulated in-vitro systems, which lying stroma [4], suggesting altered expression of facilitates mechanistic insights by connecting the exper- multiple genes. We review studies that have applied imental state with the in-vivo state [5]. When applied to microarray technology to sinonasal polyps to monitor nasal polyps, gene-expression profiling has a potential to expression of thousands of genes, and thereby gain define expression signatures that characterize patient insights into putative mechanisms of and novel targets subgroups within the currently heterogeneous clinical for sinonasal polyposis, CRS, and asthma. groups, predict response to various treatments, and offer novel therapeutic targets. Gene-expression profiling in nasal polyps Several reports [6–11] have applied microarray technol- Gene-expression profiling is a method of monitoring ogy to sinonasal tissues to examine expression of either a expression of thousands of genes simultaneously on a limited set of genes within small patient populations or to 1528-4050 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/ACI.0b013e32831d8170 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Copyright © LippincottWilliams& Wilkins.Unauthorized reproductionofthisarticle isprohibited. 24 Upper airway disease Table 1 Summary of published work using microarrays to study human sinonasal polyps Reference Expression microarray Tissue (n ¼ number of patients) Highlighted genes Method of validation Fritz et al. [10] HuGeneFL (Affymetrix, Santa Clara, Allergic rhinitis without polyps (n ¼ 4) Mammaglobin increased in polyps qRT-PCR California, USA); 5600 full-length vs. allergic rhinitis with polyps (n ¼ 3) human genes Liu et al. [11] GeneChip HG-U95Av2 (Affymetrix); Polyps from CRS treated with intranasal Statherin, PIP, lactoferrin, DMBT1 increased qRT-PCR, IHC 10 000 full-length genes steroids for more than a month (n ¼ 10) in polyps; CC10 (uteroglobin) decreased vs. controls mucosa (n ¼ 4); of the in polyps CRS patients, three were allergic, five had asthma, and two had aspirin sensitivity Benson et al. [12] HuGe-133A (Affymetrix); 22 283 genes Polyps from CRS (n ¼ 4) before vs. after Uteroglobin increased in treated vs. untreated qRT-PCR, IHC topical fluticasone treatment; excluded polyps, decreased in untreated polyps vs. patients with asthma, cystic fibrosis, healthy mucosa; mammaglobulin B increased ciliary dyskinesia, and smoke exposure in treated vs. untreated polyps Wang et al. [6] BionstarH-IC (United Gene Holdings, Polyps from CRS (n ¼ 4) vs. controls from 17 increased in polyps; IL-17R increased WB, IHC Shanghai, China); 491 genes inferior turbinates mucosa (n ¼ 4); one in polyps patient was allergic, none had asthma or aspirin sensitivity Figueiredo et al. [7] Human Q-series cytokines (SuperArray Nonallergic polyps and inflamed mucosa from TGFb1 increased in inflamed mucosa; IL-5 qRT-PCR Corp., Maryland, USA); 96 genes patients with CRS (n ¼ 21) vs. healthy increased in polyps controls; all samples for each group were pooled and two microarrays hybridized; excluded allergic asthma, allergic rhinitis, cystic fibrosis, primary ciliary dyskinesia, and steroid use Orlandi et al. [9] Spotted cDNA array (Amersham Polyps from patients with AFS (n ¼ 4) and Sialyltransferase 1 increased in EMRS; GM2 qRT-PCR Biosciences, Piscataway, New Jersey, EMRS (n ¼ 3) ganglioside activator protein and S100 USA) 6912 unique cDNA clones calcium-binding protein increased in EMRS Bolger et al. [8] Human asthma gene array (SuperArray, Nasal polyps before (n ¼ 10) and after (n ¼ 7) Chemokine and leukotriene receptor genes None Inc.) 89 genes oral corticosteroid treatment in the same expressed at high levels in pretreated polyps patients; excluded patients with cystic and changed after corticosteroids fibrosis or systemic granulomatous disease Liu et al. [13] HG-U133A GeneChip (Affymetrix) Polyps from patients with CRS (n ¼ 6) vs. Differential expression of IL-8 and RGS1 qRT-PCR 14 500 genes healthy controls (n ¼ 6) Stankovic et al. [14] HG-U133-plus2.0 GeneChip (Affymetrix) Polyps from patients with ASA (n ¼ 10) vs. Periostin increased in CRS and ASA; PIP qRT-PCR, IHC 47 000 transcripts polyps from patients with CRS (n ¼ 10) vs. decreased in CRS and ASA; MET increased healthy controls (n ¼ 10) in CRS, not ASA, AZGP1 decreased in CRS and ASA; PP1R9B increased in CRS, not ASA AFS, allergic fungal sinusitis; ASA, aspirin-sensitive asthma; CRS, chronic rhinosinusitis; DMBT1, deleted in malignant brain tumor protein 1; EMRS, eosinophilic mucin rhinosinusitis; IHC, immunohistochemistry; PIP, prolactin-induced protein; PP1R9B, protein phosphatase 1 regulatory subunit 9B; qRT-PCR, real time quantitative reverse transcription-PCR; TGFb1, transforming growth factor beta 1; WB, western blot. Gene-expression signatures of nasal polyps Platt et al. 25 assay the entire human genome in small [12,13] or theory, altered MET signaling may underlie negative moderately sized [14] populations. These studies are effects of cigarette smoking on sinusitis. Increased summarized in Table 1, which outlines distinct patient expression of MET in polyps associated with CRS but populations that have been analyzed, and genes that have not ASA [14] suggests that putative therapeutic strat- been highlighted as potentially pathogenic. The wide- egies aimed at interfering with the HGF/MET pathway ranging and typically nonoverlapping results seen in [29] may be effective against a subset of nasal polyps. these studies reflect heterogeneity of the studied popu- lations, effects of therapeutic medications, differences in PP1R9B is a ubiquitously expressed gene that plays a role the number of analyzed genes, diversity in the statistical in cell growth and molecular scaffolding [30]. The exist- and bioinformatic rigor with which data were analyzed, ing protein phosphatase 1 inhibitors [31] offer potential and disparity in the methods and extent of data vali- novel treatments for CRS. dation. The challenge has been to obtain meaningful results from a large volume of data generated
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