5685

Chromosomal instability is a hallmark of carcinogenesis and generates gene copy changes in the cancer cell. For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical cancer, 36 primary cervical squamous cell carcinoma (SCC) samples and 10 cell lines originating from cervical SCC were initially screened by array comparative genomic hybridization. Collectively, the most frequent gains were located on 5p15.2 - 14.3 (59%), 5p13.3 (65%) and 5p13.2 - 13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04) and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in-situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3% and 54.5% for OSMR, PDZK3 and TRIO respectively, with OSMR gain adversely influencing overall patient survival independently of tumour stage (p = 0.046). We further demonstrate in the cervical SCC cell line CaSki that exogenous OSM activates downstream-signaling elements of OSMR including STAT3, p44/42 MAPK and S6 ribosomal protein. Moreover, VEGF, a key angiogenic factor known to be inducible by the JAK-STAT pathway, was increased in CaSki following OSM stimulation and inhibited by OSMR depletion, suggesting one mechanism by which OSMR overexpression may mediate the adverse overall survival that was observed. In addition, the colonies formed by CaSki following OSMR depletion had appearances suggestive of reduced cellular motility, an observation further extended by evidence of significantly reduced invasiveness of OSMR-depleted CaSki cells in a matrigel Boyden chamber. In conclusion, we have obtained genomic and in vitro functional data that copy number driven overexpression of OSMR contributes to the malignant phenotype of cervical SCC. As OSMR copy number is increased in a large proportion of SCC in vivo, with copy number gain being associated with adverse clinical outcome, the gene is a potential prognostic biomarker. OSMR copy number and/or expression levels may indicate whether therapy should be intensified or can be used at reduced doses, thereby decreasing overall toxicity. Moreover, as a cell surface growth factor receptor, OSMR may represent a candidate for targeted therapy of cervical SCC.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA