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Identification of a Gene Signature for Rapid Screening of Oral Squamous Cell Carcinoma Amy F

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Identification of a Gene Signature for Rapid Screening of Oral Squamous Cell Carcinoma Amy F Human Cancer Biology Identification of a Gene Signature for Rapid Screening of Oral Squamous Cell Carcinoma Amy F. Ziober,1Kirtesh R. Patel,1Faizan Alawi,3 Phyllis Gimotty,4 Randall S. Weber,6 Michael M. Feldman,2 Ara A. Chalian,1Gregory S. Weinstein,1Jennifer Hunt,5 and Barry L. Ziober1 Abstract Purpose: Oral cancer is a major health problem worldwide and in the U.S. The 5-year survival rate for oral cancer has not improved significantly over the past 20 years and remains at f50%. Patients diagnosed at an early stage of the disease typically have an 80% chance for cure and functional outcome, however, most patients are identified when the cancer is advanced. Thus, a convenient and an accurate way to detect oral cancer early will decrease patient morbidity and mortality. The ability to noninvasively monitor oral cancer onset, progression, and treatment outcomes requires two prerequisites: identification of specific biomarkers for oral cancers as well as noninvasive access to and monitoring of these biomarkers that could be conducted at the point of care (i.e., practitioner’s or dentist’s office) by minimally trained personnel. Experimental Design: Here, we show that DNA microarray gene expression profiling of matched tumor and normal specimens can identify distinct anatomic site expression patterns and a highly significant gene signature distinguishing normal from oral squamous cell carcinoma (OSCC) tissue. Results: Using a supervised learning algorithm, we generated a 25-gene signature for OSCC that can classify normal and OSCC specimens. This 25-gene molecular predictor was 96% accurate on cross-validation, averaging 87% accuracy using three independent validation test sets and failing to predict non ^ oral tumors. Conclusion: Identification and validation of this tissue-specific 25-gene molecular predictor in this report is our first step towards developing a new, noninvasive, microfluidic-based diagnostic technology for mass screening, diagnosis, and treatment of pre-OSCC and OSCC. Head and neck cancers are the sixth most common cancer cell carcinoma (OSCC) remains at f50% (2–4). In addition, worldwide and are associated with low survival and high aggressive treatment of OSCC cancer is controversial because it morbidity (1). Cancers of the oral cavity account for 40% of can lead to severe disfigurement and morbidity (5). As a result, head and neck cancers and include squamous cell carcinomas many patients with OSCC cancers are either overtreated or of the tongue, floor of the mouth, buccal mucosa, lips, hard undertreated, with significant personal and socioeconomic and soft palate, and gingiva (2, 3). Despite therapeutic and effects. diagnostic advances, the 5-year survival rate for oral squamous One of the fundamental factors accounting for the poor outcome of patients with OSCC is that a great proportion of oral cancers are diagnosed at advanced stages, and therefore, treated late. Early detection of oral cancer lesions will greatly 1 Authors’Affiliations: Departments of Otorhinolaryngology-Head and Neck improve morbidity associated with late disease treatment and Surgery, 2Pathology and Laboratory Medicine, 3Department of Pathology, School 4 overall patient survival. For example, early detection could lead of Dental Medicine, and Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Health System, to frequent patient monitoring, dietary changes, counseling on Philadelphia, Pennsylvania; 5Department of Pathology, University of Pittsburgh and cessation of smoking and drinking, preventative drug School of Medicine, Pittsburgh, Pennsylvania; and 6Department of Head and Neck administration, and/or lesion removal. As such, early diagnosis Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas and treatment of OSCC has been shown to lead to mean Received 3/6/06; revised 5/21/06; accepted 5/25/06. Grant support: NIH grants DE15856-01and DE015626-01(B.L. Ziober). survival of >80% and a good life quality after treatment (6). The costs of publication of this article were defrayed in part by the payment of page However, no methodology exists that could early, accurately, charges. This article must therefore be hereby marked advertisement in accordance and easily mass screen for oral cancer lesions. with 18 U.S.C. Section 1734 solely to indicate this fact. Currently, clinical examination and histopathologic studies Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). are the standard diagnostic methods used to ascertain whether Requests for reprints: Barry L. Ziober, Molecular Tumor Biology Laboratory, biopsied material are precancerous or cancerous lesions (7). Department of Otorhinolaryngology-Head and Neck Surgery, University of Biopsies are invasive procedures typically involving surgical Pennsylvania Health System, 5 Silverstein/Ravdin, 3400 Spruce Street, techniques. Furthermore, biopsies are limited when it comes to Philadelphia, PA 19104. Phone: 215-898-0075; E-mail: bziober@ mail. med.upenn.edu. lesion size. For example, small lesions may not provide enough F 2006 American Association for Cancer Research. material for accurate diagnosis, whereas biopsies taken from doi:10.1158/1078-0432.CCR-06-0535 large lesions may not accurately reflect every histopathologic Clin Cancer Res 2006;12(20) October 15, 2006 5960 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Identification of a Gene Signature for Rapid Screening of OSCC aspect of the lesion. Finally, the biopsy, as a diagnostic tool, has cells will require easy access to the site in which these cancers limited sensitivity. Thus, additional methodologies would be typically arise, as well as a readily available source of cells. Oral helpful in screening for premalignant and malignant oral cavity saliva meets both of these criteria. A fundamental cancer lesions. However, to noninvasively detect oral cancer requirement to identify cancer lesions early, accurately, and Fig. 1. Gene expression profiles of 13 normal oral mucosal and 13 patient-paired OSCC specimens shows distinct separation. A total 2,207 genes were identified after the microarray data was normalized, filtered for only the genes present, and analyzed using ANOVA with Benjamini-Hochberg multiple testing correction factor at P V 0.05. A, to visualize the data, samples and genes were analyzed by unsupervised hierarchical clustering using Cluster and graphically represented inTreeview (17). Gene signatures of interest are highlighted by dark lines.Tree headings for tumor and normal specimens are labeled. B, two major classes of samples were identified using the 2,207 genes identified in (A) representing an exact separation of the tumor and normal specimens.Tree headings for these two groups are labeled. Anatomic sites in the oral cavity in which samples were surgically removed are labeled as well as the stage and tissue number. Samples are subclustered into tongue and non-tongue classes under each of the tumor and normal headings. www.aacrjournals.org 5961 Clin Cancer Res 2006;12(20) October 15, 2006 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Human Cancer Biology Fig. 2. Unsupervised classification analysis of patient-matched normal oral mucosal and OSCC samples. A, principal components analysis was done on tongue and non-tongue oral cavity OSCC and normal samples. Perspective image with the tongue and non-tongue samples as principal components and axes.Tongue (n), and non-tongue samples ( ), clustering of similar samples (encircled points). easily from the cellular population in saliva requires the fluidic ‘‘lab-on-a-chip’’ system for rapid (real-time), point-of- identification of unique biomarkers. care detection and diagnosis of oral cancer. Typically, genetic changes in cancer cells lead to altered gene expression patterns that can be identified long before the cancer phenotype has manifested. When compared with normal Materials and Methods mucosa, those changes that occur in the cancer cell can be used as biomarkers. Attempts to find biomarkers that identify Patient samples and characteristics. Consent was obtained for all premalignant OSCC and cancerous lesions have resulted in patients in this study in accordance with guidelines set forth by the several candidate genes associated with OSCC tumor progres- Institutional Review Board at the University of Pennsylvania and the University of Pittsburgh. All matched patient normal and tumor sion including p53, cyclin D1, and epidermal growth factor samples and unmatched normal and tumor samples were obtained receptor (8, 9). However, to date, no single gene has shown from surgical resection specimens from patients undergoing surgery for sufficient diagnostic utility in OSCC. Thus, as in many other OSCC using standardized procedures. The Penn data set was isolated cancers, clinical diagnosis will require considering the com- and microarrayed at the University of Pennsylvania, whereas the RO bined influence of many genes. Not surprisingly, the expression data set was kindly provided by Dr. Ruth Muschel (Children’s Hospital patterns of many genes have shown dramatic correlations with of Philadelphia, Philadelphia, PA) and has been previously reported tumor behavior and patient outcome. Indeed, microarray (12). The OSCC data set and other
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