1175

We used the high-throughout genome profiling method Representational Oligonucleotide Microarray Analysis (ROMA) to identifygenomic copy number changes of potential biologic significance in 15 xenograft enriched samples of pancreatic cancer representing three primary carcinomas and 11 matched metastases from four different patients. Although all samples from all four patients demonstrated marked genomic instability, evidence of the clonal relatedness was evident by identical copy number gains or losses among matched samples. Most copy number alterations involved chromosomes previously implicated in pancreatic carcinogenesis including deletions of 18q (SMAD4/DPC4) and 9p (CDKN2A/p16) and/or amplifications of 8q (c-MYC). However, in one primary carcinoma and matched metastasis a 0.36-Mb amplification at 18q11.2 was identified that contained only two known genes, GATA-6 and cTAGE1. This amplification was further confirmed by FISH and found in an additional 10 of 44 (23%) pancreatic carcinomas analyzed. Combined genetic and transcriptional analyses showed consistentoverexpression of GATA-6 in 27 of 33 (82%) pancreatic cancers examined independent of the presence of 18q11.2 amplification. By contrast, overexpression of cTAGE1 was only found in 5 of these same 33 (15%) samples suggesting GATA-6 is the true target of this amplification. Forced overexpressionof the GATA-6 gene stimulated in vitro cell proliferation, enhanced anchorage-independentgrowth and as well as promoted tumor growth in vivo. Taken together, our data indicate that amplification and overexpression of the intestinal transcriptional factor GATA-6 may play an important role in pancreatic carcinogenesis.

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