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

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.

TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target

“…30 The implication of Twist1 in cell migration is attributed primarily to its ability to contribute to EMT, eg, through the down-regulation of E-cadherin and the upregulation of mesenchymal markers like vimentin, fibronectin, and N-cadherin, as noted above. [1][2][3][4][5]7,26,27,31 Previous studies have indicated that Twist1 promotes cell proliferation, migration, and expression of a primitive ECM, thus promoting an undifferentiated state. 31 In addition, Twist1 contributes to the EMT phenotype, which has been associated with resistance to chemotherapy and relapses.…”

Gene expression profiling of archival tongue squamous cell carcinomas provides sub-classification based on DNA repair genes

“…EGFR, BRCA2 and SERPINE1, which showed over-expression in a fraction of the tumour samples, were analyzed in three tumour samples over-expressing the gene (1-3), three tumour samples not over-expressing the gene (4-6) and three control samples (7)(8)(9). BCL2A1 showing a more general over-expression in most tumour samples was analyzed in four random tumour samples (1-4) and four controls (5)(6)(7)(8). All expression values were normalized to the internal control gene TUBA6.…”

“…High biological and prognostic diversity has been seen between SCCHN tumours originating from different sites (3)(4)(5). Tumours of the tongue are reported to have a unique gene expression pattern making it possible to separate them from other tumours in the oral cavity (6), emphasizing the need for site-specific studies. An increase in SCCHN in young adults, particularly tumours affecting the tongue, has been reported from many parts of the world including Scandinavia (7)(8)(9)(10).…”

A Novel Function of CXCL13 to Stimulate RANK Ligand Expression in Oral Squamous Cell Carcinoma Cells

“…RANKL is a critical osteoclastogenic factor in the bone microenvironment (7). Microarray analysis for gene expression profiling in OSCC identified gene signatures that include chemokine (CXC motif) ligand-13 (CXCL13) that is implicated in OSCC development and progression (5). Recent evidence indicated that down-regulation of CXCL5 expression inhibits head and neck squamous cell carcinoma development and invasion (15).…”

“…Chemokines are implicated in tumor progression and metastasis (4). More recently, gene expression profiling studies implicated chemokine ligand-13 (CXCL13) in OSCC tumor development/progression (5). CXCL13 (BCA-1) that binds monogamously to the CXCR5 receptor is involved in B-cell chemotaxis (6).…”