Abstract
Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.
Highlights
Pancreatic cancer has among the highest mortality rates of any cancer, pointing to a critical need for more effective therapies
We report here the discovery of amplification of the GATA6 gene in many human pancreatic cancers
Our discovery of GATA6 amplification provides a new foothold into understanding the pathogenic mechanisms underlying pancreatic cancer, and suggests new strategies for therapy by targeting GATA6 or the genes it regulates
Summary
Pancreatic cancer has among the highest mortality rates of any cancer, pointing to a critical need for more effective therapies. While much progress has been made in understanding pancreatic cancer pathogenesis, a more comprehensive characterization of molecular genetic alterations is needed to define new molecular targets and therapeutic opportunities [1]. Genomic DNA copy number alterations (CNAs) are frequent in pancreatic cancer, where they alter the dosage and expression of cancer genes. Amplified oncogenes include KRAS ( commonly activated by point mutation), AKT2 and MYB. Likewise, deleted tumor suppressor genes (TSGs) include CDKN2A, TP53 and SMAD4 ( inactivated by mutation and promoter hypermethylation) [2]. Mapping CNAs has become an important starting point for discovering new cancer genes, and led to the original identification of CDKN2A and SMAD4 as TSGs [3,4]
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