Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma

Fu, Baojin; Luo, Mingde; Lakkur, Sindhu; Lucito, Robert; Iacobuzio‐Donahue, Christine A.

doi:10.4161/cbt.7.10.6565

Cited by 69 publications

(73 citation statements)

References 34 publications

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“…Interestingly, Kwei et al (36) and Fu et al (37) reported that 18q11.2 gain/amplification with overexpression of GATA6 is detected in 9-19% of pancreatic carcinomas. Both the pancreas and distal esophagus are derived from the embryonic endodermal foregut, making it plausible that these two tumors may share a common lineage-survival oncogene.…”

Section: Discussionmentioning

confidence: 99%

Activation of GATA binding protein 6 ( GATA6 ) sustains oncogenic lineage-survival in esophageal adenocarcinoma

Lin¹,

Bass

Lockwood

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Gene amplification is a tumor-specific event during malignant transformation. Recent studies have proposed a lineage-dependency (addiction) model of human cancer whereby amplification of certain lineage transcription factors predisposes a survival mechanism in tumor cells. These tumor cells are derived from tissues where the lineage factors play essential developmental and maintenance roles. Here, we show that recurrent amplification at 18q11.2 occurs in 21% of esophageal adenocarcinomas (EAC). Utilization of an integrative genomic strategy reveals a single gene, the embryonic endoderm transcription factor GATA6 , as the selected target of the amplification. Overexpression of GATA6 is found in EACs that contain gene amplification. We find that EAC patients whose tumors carry GATA6 amplification have a poorer survival. We show that ectopic expression of GATA6 , together with FGFR2 isoform IIIb, increases anchorage-independent growth in immortalized Barrett's esophageal cells. Conversely, siRNA-mediated silencing of GATA6 significantly reduces both cell proliferation and anchorage-independent growth in EAC cells. We further demonstrate that induction of apoptotic/anoikis pathways is triggered upon silencing of GATA6 in EAC cells but not in esophageal squamous cells. We show that activation of p38α signaling and up-regulation of TNF-related apoptosis-inducing ligand are detected in apoptotic EAC cells upon GATA6 deprivation. We conclude that selective gene amplification of GATA6 during EAC development sustains oncogenic lineage-survival of esophageal adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Activation of GATA binding protein 6 ( GATA6 ) sustains oncogenic lineage-survival in esophageal adenocarcinoma

Lin¹,

Bass

Lockwood

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Overexpression of these genes has been reported in several human cancers, including pancreatic cancer (GATA6; ref. 33), B-cell chronic lymphocytic leukemia (B-CLL) and follicular lymphoma (PRKCB; ref. 34), and liver cancer (IGFBP5; ref.…”

Section: Smchd1 Deficiency Leads To Increased Clonogenicity Of Premalmentioning

confidence: 99%

Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor

Leong

Chen

et al. 2013

Cancer Research

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SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Em-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Em-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers. Cancer Res; 73(5);

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“…Such studies have led to the identification of new pancreatic cancer genes, including, for example, PAK4 (11,12) and GATA6 (13,14), validating the utility of an agnostic, genome-wide approach.…”

mentioning

confidence: 99%

Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer

Shain

Giacomini

Matsukuma

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

198

189

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Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational "hills" in the genomic landscape, together they affected at least one-third of all pancreatic cancers, defining SWI/SNF as a major mutational "mountain." Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNFintact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer.comparative genomic hybridization array | cancer gene discovery | tumor suppressor P ancreatic ductal adenocarcinoma, more commonly known as pancreatic cancer, remains a leading cause of cancer deaths in the developed world (1, 2). Each year, the number of patients diagnosed with pancreatic cancer is nearly equal to the number that will die from the disease, underscoring the inadequacy of current therapies. Indeed, the overall 5-y survival rate is less than 5% (3). A more complete characterization of its molecular pathogenesis may suggest new avenues for targeted therapy.Much has been learned of the molecular genetic alterations underlying pancreatic cancer (reviewed in 4, 5). Early events, identified in early precursor lesions [pancreatic intraepithelial neoplasia (PanIN)], include activational mutation (and/or amplification) of the KRAS2 oncogene, occurring in 75-90% of pancreatic cancers, and inactivation of the CDKN2A (p16 INK4A ) cell-cycle regulator in 80-95% of cases. Later events (identified in more advanced PanIN) include inactivation of the TP53 tumor suppressor in 50-75% of pancreatic cancers, and loss of SMAD4 (DPC4) in 45-55% of cases.

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Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma

Cited by 69 publications

References 34 publications

Activation of GATA binding protein 6 ( GATA6 ) sustains oncogenic lineage-survival in esophageal adenocarcinoma

Activation of GATA binding protein 6 ( GATA6 ) sustains oncogenic lineage-survival in esophageal adenocarcinoma

Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor

Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer

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