Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers, with approximately 400,000 new cases and 200,000 deaths worldwide in 2008 (http://www-dep.iarc.fr/
). Approximately 40,000 new cases and almost 8,000 deaths from OSCC are estimated to occur in the United States in 2012 
. The overall 5-yr survival rate of OSCC patients is approximately 60% 
. The prognosis of OSCC patients is adversely influenced by the development of recurrent cancer, which occurs in 5–50% of patients 
. Better prediction of which patients are most at risk for recurrence or disease progression is needed. Several factors have been found to be predictive of the development of recurrent OSCC, including tumor stage, tumor depth, nodal status, lymphovascular or perineural invasion, positive surgical margins, and extracapsular spread 
. However, further improvement in the prediction of risk for recurrence or disease progression could help physicians identify patients who need more aggressive treatment or more frequent follow-up. Genes that play roles in the progression of normal tissue to cancer may serve as markers to predict recurrence or disease progression of OSCC patients.
Based on the field cancerization concept proposed by Slaughter et al in 1953 
, the changes in the mucosa of the entire upper aerodigestive tract may be the result of long term exposure to carcinogens and may explain the occurrence of local recurrence or second primary disease. The field cancerization concept was supported by subsequent studies which found abnormal histologic and molecular features in the uninvolved, clinically normal, oral mucosae of OSCC patients 
. A number of studies have shown alterations at a molecular level, such as loss of heterozygosity (LOH) at 3p, 9p, and 17p 
, gain of chromosome region 20q13.33, 7p22.2-pter, 11p15.5-pter, and 16p13.3-pter 
, and p53 mutation 
in the uninvolved oral mucosae, either adjacent to or distant from the tumor of OSCC patients. There is also evidence of increased expression of some genes such as epidermal growth factor receptors 
, cyclin D1 and mindbomb E3 ubiquitin protein ligase 1 
, and cytokeratins 
in the uninvolved oral mucosae of OSCC patients.
In addition to the studies of molecular changes in the uninvolved oral mucosae of OSCC patients, there have been hundreds of studies reporting on the molecular changes in the oral cancer tissues, either at an individual gene level or a genome-wide level. For example, there have been reports of LOH on Chromosome 1p31, 3p25-p26, 4q25, 5q21-22, 8p21-23, 9p21-22, 10 at D10S202 and DD10S217, 11q, 14q, 17p, 20q12-13.1, and 21q11.1 in OSCC samples 
. Studies using array comparative genomic hybridization (CGH) further expand the knowledge of gains and losses of chromosomal regions across the genome. Gains at chromosomal regions 1q23, 3q23, 3q26, 5p15.2, 5p15.33, 7p11, 7p12.3-13, 7p22.3, 7q21.2, 7q35, 8q21.1-24.3, 8q24, 9q34.3, 11q13, 14q23,16p13.3, 19q12, 19q13, 20q13, and losses at 2p15, 3p21-3p12, 3p22, 3p14, 4q34.3, 4q35.2, 8p32,10p12, 16q23.2, 18q21-q23 in OSCC samples have been detected using array CGH 
. Several researchers have used proteomics to identify diagnostic 
or prognostic 
biomarkers for OSCC; however, these studies were either small or had no external validation.
With the advent of a high-throughput microarray technology, investigation of gene expression on a genome-wide level has become feasible and routine. Microarray studies usually result in a list of many genes; further definition of the functions of or pathways involving these genes could provide additional knowledge about OSCC. A gene expression profile, if validated in multiple, well-designed, independent studies, could also be developed as a useful clinical test as demonstrated for breast cancer 
. Prior studies, including ours, have reported many genes differentially expressed between OSCC and normal tissue 
. However, these studies compared OSCC to either uninvolved oral mucosae of OSCC patients or normal oral mucosae from people without cancer. To the best of our knowledge, no study has compared genome-wide gene expression profiles of normal oral mucosae from non-cancerous patients, uninvolved oral mucosae from OSCC patients, and OSCC samples in the same study. As proposed by Braakhuis 
, oral carcinogenesis can be viewed as a multistep process; from normal tissue to a patch, which progresses to a field, and finally to an invasive carcinoma with additional genetic alterations in each step. Identifying the changes in gene expression in these steps may help advance our understanding of the disease progression process and lead to discovery of markers to predict disease progression. The purpose of the current study is to identify genes that are dysregulated in uninvolved oral mucosae from OSCC patients compared with normal oral mucosae from patients without cancer, and show further dysregulation in cancer tissue. We believe that these genes may play an important role in the progression of OSCC, and we tested our hypothesis by determining whether the expressions of dysregulated genes are associated with disease progression or OSCC-specific mortality.