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Application of Pathway Analysis to Understand Oral Cancer Genome

Ivy F.L. Tsui1, 2,(itsui@bccrc.ca); Lewei Zhang3, Miriam P. Rosin1, and Wan L. Lam1, 2.1British Columbia Cancer Research Centre, 2Departments of Pathology and Laboratory medicine and 3Oral Biological and Medical Sciences, University of British Columbia, Canada

Content: The development of high-throughput DNA microarray analysis has allowed whole genome profiling of oral cancer lesions, enabling the identification of genetic markers that correlate with oral tumours. Since tumours often exhibit increased genomic instability, it is critical to evaluate oral premalignant lesions (OPLs) in order to understand the causal events that lead to carcinogenesis. Because multiple pathways are disrupted to contribute to cancer phenotypes, the integration of network analysis will help us to decipher the pathways that are responsible for oral carcinogenesis.

Technology: The submegabase-resolution tiling set (SMRT) array comparative genomic hybridization (CGH) was employed to investigate genomic alterations in 25 OPLs graded as severe dysplasias and carcinoma in situ. The SMRT array allows the identification of alterations as small as 0.08 Mbp. Computational multiple alignment of genomic profiles and the identification of DNA aberrations were performed using the SeeGH software technology platform.

Design: Multiple genetic alterations in the same pathway might essentially lead to the same downstream phenotype. Focusing on pathway analysis will dramatically minimize the number of candidate. Using this approach, minimal altered regions are identified and all genes within those regions are flagged. These genes are then analyzed by Pathway-Express, software that automatically searches the KEGG (Kyoto Encyclopedia of Genes and Genomes) database and visualize the genes of interest in the associated pathways. All altered genes are differentially colored in the KEGG pathway map.

Results: From this analysis approach, 18 KEGG pathways are shown to be disrupted in OPLs. Among these include the MAPK signaling pathway, which contains 14 of the differentially expressed gene acting in this one single pathway. Additionally, important cancer pathways, including the Jak-STAT signaling, Wnt signaling, cell cycle, and apoptosis pathways are also shown to be disrupted. 

Conclusions: This study demonstrates the feasibility of evaluating the disruption of pathway components systematically by querying segmental DNA alteration profile.  This provides an integrative view of the disturbed biological processes in the oral cancer genome, and helps us to target the multiple disrupted pathways to develop appropriate treatments for oral cancer.