Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer.
Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer.
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DOI：
10.1371/journal.pgen.1000081
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发表时间：
2008-05-23
期刊：
影响因子：
4.5
通讯作者：
Pollack JR
中科院分区：
文献类型：
--
作者：
Kwei KA;Bashyam MD;Kao J;Ratheesh R;Reddy EC;Kim YH;Montgomery K;Giacomini CP;Choi YL;Chatterjee S;Karikari CA;Salari K;Wang P;Hernandez-Boussard T;Swarnalata G;van de Rijn M;Maitra A;Pollack JR
胰胆管癌是所有癌症类型中死亡率最高的。发现分子遗传改变的全谱可能为治疗提供新的途径。为了对基因组改变进行分类，我们对31例外分泌胰腺癌和6例远端胆管癌进行了基于阵列的基因组分析，这些癌作为异种移植物扩增以富集肿瘤细胞部分。我们确定了许多局灶性DNA扩增和缺失，包括19%的胰胆病例在细胞带18q11.2处获得，这是一个在其他肿瘤类型中不常见的扩增位点。在18q11.2最小的共享扩增包括GATA 6，一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，并且在54例原发性胰腺癌中的25例（46%）中观察到强免疫染色，而在33例正常胰腺标本中观察到0例。异种移植物中的GATA 6表达与特定的微阵列基因表达模式相关，富含加塔结合位点和线粒体氧化磷酸化活性。siRNA介导的GATA 6在胰腺癌细胞系中的敲低与扩增导致细胞增殖、细胞周期进展和集落形成减少。我们的研究结果表明，GATA 6扩增和过度表达有助于胰腺癌细胞的致癌表型，并确定GATA 6作为候选谱系特异性癌基因在胰胆管癌，与新的治疗策略的影响。胰腺癌是一种毁灭性的疾病，在所有癌症中生存率最低。更好地了解胰腺癌的分子基础可能会导致改善合理的治疗。我们在此报告了在许多人胰腺癌中发现的GATA 6基因扩增（即额外拷贝）。GATA 6是正常胰腺发育中基因表达和功能的调节剂。我们的研究结果表明，它的扩增和异常过表达有助于胰腺癌的发展。GATA 6加入了一个不断增长的癌症基因列表，这些基因在正常人类发育中起关键作用，但在异常表达时在癌症中起致病作用。我们对GATA 6扩增的发现为了解胰腺癌的致病机制提供了一个新的立足点，并提出了通过靶向GATA 6或其调控的基因进行治疗的新策略。
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. Pancreatic cancer is a devastating disease, having among the lowest survival rates of any cancer. A better understanding of the molecular basis of pancreatic cancer may lead to improved rationale therapies. We report here the discovery of amplification (i.e. extra copies) of the GATA6 gene in many human pancreatic cancers. GATA6 is a regulator of gene expression and functions in the development of the normal pancreas. Our findings indicate that its amplification and aberrant overexpression contribute to pancreatic cancer development. GATA6 joins a growing list of cancer genes with key roles in normal human development but pathogenic roles in cancer when aberrantly expressed. 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.
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斯坦福微阵列数据库：新分析工具的实现和软件的开源发布。
影响因子：
14.9
作者：
Demeter, Janos;Beauheim, Catherine;Gollub, Jeremy;Hernandez-Boussard, Tina;Jin, Heng;Maier, Donald;Matese, John C.;Nitzberg, Michael;Wymore, Farrell;Zachariah, Zachariah K.;Brown, Patrick O.;Sherlock, Gavin;Ball, Catherine A.
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Ball, Catherine A.
影响因子：
64.8
作者：
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通讯作者：
Flavell, RA
影响因子：
11.2
作者：
Heidenblad, M;Schoenmakers, EFPM;Höglund, M
通讯作者：
Höglund, M
影响因子：
11.2
作者：
Iacobuzio-Donahue, CA;van der Heijden, MS;Kern, SE
通讯作者：
Kern, SE
影响因子：
48
作者：
Birmingham, A;Anderson, EM;Khvorova, A
通讯作者：
Khvorova, A