Genome profiling of pancreatic adenocarcinoma. Genes Chromosomes Cancer

Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR891 Inserm, Institut Paoli-Calmettes, Marseille, France.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 06/2011; 50(6):456-65. DOI: 10.1002/gcc.20870
Source: PubMed


Pancreatic adenocarcinoma is one of the most aggressive human cancers. It displays many different chromosomal abnormalities and mutations. By using 244 K high-resolution array-comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine-needle aspirations from pancreatic adenocarcinoma and eight human adenocarcinoma pancreatic cell lines. Using both visual inspection and GISTIC analysis, recurrent losses were observed on 1p, 3p, 4p, 6, 8p, 9, 10, 11q, 15q, 17, 18, 19p, 20p, 21, and 22 and comprised several known or suspected tumor suppressor genes such as ARHGEF10, ARID1A, CDKN2A/B, FHIT, PTEN, RB1, RUNX1-3, SMAD4, STK11/LKB1, TP53, and TUSC3. Heterozygous deletion of the 1p35-p36 chromosomal region was identified in one-third of the tumors and three of the cell lines. This region, commonly deleted in human cancers, contains several tumor suppressor genes including ARID1A and RUNX3. We identified frequent genetic gains on chromosome arms 1q, 3q, 5p, 6p, 7q, 8q, 12q, 15q, 18q, 19q, and 20q. Amplifications were observed in 16 tumors. AKT2, CCND3, CDK4, FOXA2, GATA6, MDM2, MYC, and SMURF1 genes were gained or amplified. The most obvious amplification was located at 18q11.2 and targeted the GATA6 gene, which plays a predominant role in the initial specification of the pancreas and in pancreatic cell type differentiation. In conclusion, we have identified novel biomarkers and potential therapeutic targets in pancreatic adenocarcinoma.

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    • "These occur in approximately 50% of endometriosis-associated ovarian clear cell (OCCC) and 30% of endometrioid ovarian carcinomas (EnOC) [3, 4], in endometrial carcinomas, with a loss of expression in 20-30% depending on the histological subtype [5, 6], as well as in breast carcinomas (mutations in 4-35%) [7, 8]. Non-gynecological carcinomas with frequent ARID1A mutations include pancreatic carcinomas (mutations in 8-45%) [9, 10], gastric adenocarcinomas (mutations in 8-29%) [11-13], hepatocellular carcinomas (mutations in 10-17%) [14-16], as well as clear cell renal cell carcinomas [17, 18]. The majority of the mutations lead to a loss of the ARID1A encoded protein [3], also referred to as BAF250a or p270, which is a subunit of the SWI/SNF chromatin remodeling complex [2]. "
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    ABSTRACT: ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.
    Oncotarget 06/2014; 5(14). DOI:10.5167/uzh-106117 · 6.36 Impact Factor
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    • "In addition, tissues with up-regulation of eIF5A2 also show high levels of DHS and DOHH at the transcript level [37], indicating constitutive activation of eIF5A2 synthesis and hypusination resulting in increased protein synthesis and cell growth in HCC. Utilizing comparative genomic hybridization and copy number variation analysis, chromosome 3q is amplified in HCC [38], as well as in several cancers including pancreatic [36, 39], esophageal [40, 41], prostate [42], lung [32, 43], gastric [44, 45], ovarian [33, 46] and colorectal [30, 47] cancer. Thus, the aberrant expression of eIF5A2, also residing on chromosome 3q, is more frequently observed than that of eIF5A1 and this may at least partially explain for the aberrant expression of eIF5A2 in HCC. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a primary liver malignancy and accounts for most of the total liver cancer cases. Lack of treatment options and late diagnosis contribute to high mortality rate of HCC. In eukaryotes, translation of messenger RNA (mRNA) to protein is a key process in protein biosynthesis in which initiation of translation involves interaction of different eukaryotic translation initiation factors (eIFs), ribosome subunits and mRNAs. Eukaryotic translation initiation factor 5A (eIF5A) is one of the eIFs involved in translation initiation and eIF5A2, one of its isoforms, is upregulated in various cancers including HCC as a result of chromosomal instability, where it resides. In HCC, eIF5A2 expression is associated with adverse prognosis such as presence of tumor metastasis and venous infiltration. Based on eIF5A2 functional studies, suppressing eIF5A2 expression by short interfering RNA alleviates the tumorigenic properties of HCC cells in vitro while ectopic expression of eIF5A2 enhances the aggressiveness of HCC cells in vivo and in vitro by inducing epithelial-mesenchymal transition. In conclusion, eIF5A2 is a potential prognostic marker as well as a therapeutic target for HCC.
    09/2012; 2012:760928. DOI:10.1155/2012/760928
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    • "Other mechanisms for instability at the FRA3B site include paucity of replication initiation events [50], late replication [51], inefficient activation of origins of replication [52], and formation of RNA transcript/DNA hybrid complexes [53]. Deletions involving FHIT have been reported in small cell and non–small cell lung cancer [39], pancreatic adenocarcinoma [54], head and neck squamous cell carcinoma "
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    ABSTRACT: Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22%) than previously reported for sacral chordoma. At a similar frequency (21%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98% of sacral chordomas and 67%of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm.
    Neoplasia (New York, N.Y.) 09/2012; 14(9):788-98. DOI:10.1593/neo.12526 · 4.25 Impact Factor
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