Abstract 3007: Integrative analysis of histologically distinct oral lesions obtained from a single disease field uncovers stage-specific molecular alterations
Authors: Hughes Shevaun E. , Tsui Ivy F.L. , Poh Catherine F. , Garnis Cathie 
Published: June 2012

Oral cancer (OC) is a leading cause of cancer death worldwide, with late stage diagnosis and high recurrence rates accounting for poor survival statistics. Like many solid tumors, OC develops through a series of histopathological stages: from hyperplasia to dysplasia to carcinoma in situ (CIS) and finally to invasive cancer. While dysplastic lesions can be readily detected in clinic, they are rarely treated as only a small fraction will ultimately progress to invasive disease. By identifying the molecular mechanisms driving early malignant disease, novel tools can be developed for discriminating progression risk in early lesions and identify druggable targets that could greatly improve currently stagnant oral cancer survival rates.

Objective: To identify genes critical to early oral tumorigenesis that may also have utility as biomarkers for disease outcomes.

Methods: Fluorescence visualization techniques were used to define OC disease fields. For each patient multiple biopsies revealing distinct disease stages were simultaneously collected from within the disease field. DNA copy number (SMRT CGH), methylation (Illumina Infinium), and gene expression (Agilent 4×44K) profiles on all collected premalignant biopsies from each patient (hyperplasia, dysplasia, and CIS) were generated. Gene candidates were identified from integrated datasets based on current dogma. For example, genes exhibiting decreased expression and concurrent increased methylation, and vice versa, were flagged for further analysis. Recurring genetic and signaling cascade events were defined using Ingenuity Pathway Analysis software and validated by sequencing and expression analysis.

Results: While no DNA copy number changes were observed in dysplastic biopsies, several changes were observed in DNA methylation and gene expression data. This suggests that methylation changes may play a critical role in gene deregulation for early oral lesions. As expected, methylation and expression alterations were observed to increase with disease severity. Several genes were found to be deregulated at a frequency of &gt;50% in dysplastic lesions, strongly suggesting a critical role for these candidates in early disease development. Additional genes were recurrently altered during progression to CIS. Pathway analysis of recurrent genes candidates revealed a potential role of the wnt/β-catenin pathway and inflammation/immune response pathways in oral lesion development.

Conclusions: By leveraging high throughput platforms and a rare collection of patient-matched oral precancer tissues, we have shown that aberrant methylation is a critical mechanism driving molecular dysregulation in early oral tumorigenesis. Specific candidates identified by our integrative approach may have utility as biomarkers or therapeutic targets, ultimately helping to improve oral cancer outcomes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3007. doi:10.1158/1538-7445.AM2011-3007