Kwei Kevin A, Bashyam Murali D, Kao Jessica, Ratheesh Raman, Reddy Edumakanti C, Kim Young H, Montgomery Kelli, Giacomini Craig P, Choi Yoon-La, Chatterjee Sreejata, Karikari Collins A, Salari Keyan, Wang Pei, Hernandez-Boussard Tina, Swarnalata Gowrishankar, van de Rijn Matt, Maitra Anirban, Pollack Jonathan R
Department of Pathology, Stanford University, Stanford, California, United States of America.
PLoS Genet. 2008 May 23;4(5):e1000081. doi: 10.1371/journal.pgen.1000081.
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.
胰腺胆管癌在所有癌症类型中死亡率位居前列。发现分子遗传改变的全貌可能为治疗指明新途径。为了编目基因组改变，我们对31例胰腺外分泌癌和6例远端胆管癌进行了基于芯片的基因组分析，并将其作为异种移植进行扩展以富集肿瘤细胞部分。我们鉴定出许多局灶性DNA扩增和缺失，包括在19%的胰腺胆管病例中18q11.2细胞带出现增益，该位点在其他肿瘤类型中很少扩增。18q11.2处最小的共同扩增区域包含GATA6，这是一种先前与正常胰腺发育相关的转录调节因子。当扩增时，GATA6在mRNA和蛋白质水平均过表达，在54例原发性胰腺癌中有25例（46%）观察到强免疫染色，而在33例正常胰腺标本中未观察到。GATA6在异种移植中的表达与特定的芯片基因表达模式相关，富含GATA结合位点和线粒体氧化磷酸化活性。在具有扩增的胰腺癌细胞系中，siRNA介导的GATA6敲低导致细胞增殖、细胞周期进程和集落形成减少。我们的研究结果表明，GATA6扩增和过表达促成胰腺癌细胞的致癌表型，并将GATA6鉴定为胰腺胆管癌中候选的谱系特异性癌基因，这对新的治疗策略具有启示意义。
