Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that is disfiguring and difficult to manage with current treatment approaches. Genome-wide analysis of genetic changes that drive tumor development in HNSCC will identify molecular targets necessary for novel therapeutic development and molecular data necessary to develop new classification schemes predictive of response to those treatments. We have conducted a genome-wide analysis of genetic changes that drive tumor development in HNSCC using array comparative genomic hybridization (aCGH) at 1.5 Mb resolution to identify genetic regions that are altered in HNSCC. Over 20 matched tumor and adjacent normal tissues and 9 additional HNSCC tumors collected at the University of Pennsylvania over the past three years, and 9 HNSCC cell lines were used for this study. Both DNA and RNA were prepared in tandem. The DNA was then used to hybridize with BAC CGH arrays to identify regions of chromosomal copy number gains and losses. RNA that was prepared from the same samples was used to hybridize to Affymetrix U133A and B probe sets to identify corresponding changes in gene expression. Additional target genes of interest were further characterized using Q-PCR and Q-RT-PCR. Using these approaches we have characterized the genomic pattern of DNA alterations in HNSCC in adjacent normal tissue, primary tumor tissue and cell lines and seen that this pattern is strikingly similar, with few key differences. Using correlation analysis we have identified genomic regions that are amplified in concert. Additionally, we have characterized several genomic regions of interest in HNSCC. The first region of interest was lost in four of 28 (14%) tumor samples and maps to a 1.8 Mb region on chromosome 8p23 and contains the putative tumor suppressor CSMD1. Discordant aCGH and expression data have lead us to further characterize this loci using Q-PCR and Q-RT-PCR to determine the status of both the DNA and RNA of this gene. We have also performed detailed characterization of the telomeric region of chromosome 8q which spans the gene PTK2/FAK, previously identified as altered in several tumor types. In conclusion, we have characterized genetic changes in HNSCC at the genomic and regional levels using aCGH and expression profiling and we will further characterize the activity of potential candidate tumor suppressor genes and oncogenes in these regions. By identifying novel therapeutic targets, these studies will lay the foundation for a new era in the understanding and treatment of these devastating tumors.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]