Gene expression profiling indicates dysregulation of distinct cellular pathways in HPV positive and HPV negative oral squamous cell carcinomas
Authors: Pawadee Lohavanichbutr, John Houck, Wenhong Fan, Bevan Yueh, Eduardo Mendez, Neal Futran, D. Gregory Farwell, Melissa P. Upton, Stephen M. Schwartz, Lue Ping Zhao, Chu Chen
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

830 

Human papilloma virus (HPV) infection has been associated with the occurrence of 25-40% of squamous cell carcinomas of the oral cavity and oropharynx (OSCC). To elucidate the biological pathways involved in HPV+ vs. HPV- OSCC, we examined genome-wide gene expression profiles of newly diagnosed primary OSCC and non-malignant oral tissue from healthy controls using Affymetrix U133 plus 2.0 arrays. Tumor samples and normal oral tissue were collected in RNALater from OSCC patients and surgical patients without cancer, respectively, at three University of Washington-affiliated medical centers in Seattle, WA. HPV DNA in tissue samples was determined using the Roche Linear Array HPV Genotyping Test under a research use only agreement. Gene expression levels were computed from probe intensity values (CEL files) using the gcRMA algorithm and analyzed with estimating equations and the Ingenuity pathway analysis tool. We controlled the number of false discoveries to be fewer than 10. HPV DNA was found in 24 of 58 (41%) tumors, in every instance type 16. There were 3216 and 1952 genes, respectively, differentially expressed between HPV- or HPV+ tumors and seven HPV- controls, with 1731 overlapping between HPV- and HPV+ tumors. There were 597 genes for which the expression was statistically significantly different in the comparison of HPV- tumors vs. controls, but were not statistically significant in the comparison of HPV+ tumors vs. controls; there were 54 genes in the converse situation. While a number of cellular pathways were perturbed in both HPV+ and HPV- OSCC, there were distinct genes and pathways associated with each tumor type. Pathways that were perturbed in both tumor types included many that were known and/or implicated in cancer development: DNA synthesis and cell cycle checkpoints, immune response, angiogenesis, kinase signaling, and receptor signaling, etc. Pathways for amyloid processing, amino acid metabolism, retinol metabolism, sterol metabolism, androgen and estrogen metabolism, estrogen receptor signaling, hypoxia, EGF/PDGF/VEGF signaling, MAPK signaling, PI3K/AKT signaling, immune response, and SAPK/JNK signaling were significantly perturbed in HPV- tumors. A network of p53 associated genes and pathways showed a statistically significant involvement in HPV+ tumors. These included genes that are involved in folate biosynthesis and one carbon metabolism, chromatin assembly and nuclear stability, spindle formation during mitosis, DNA replication and repair, cellular response to therapeutics, molecular transport, and apoptosis. Apart from the possibility of some false positive associations, our study is limited by its relatively small sample size, which precluded us from evaluating the possible influence of tumor site, stage, and known risk factors for OSCC on these results. This work was supported by NCI RO1 CA095419.