Array‐CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes

Micci, Francesca; Skotheim, Rolf Inge; Haugom, Lisbeth; Weimer, Jörg; Eibak, Anne Mette; Abeler, Vera M.; Tropé, Claes G.; Arnold, Norbert; Heim, Sverre

doi:10.1002/gcc.20813

Cited by 21 publications

(25 citation statements)

References 17 publications

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“…HCDH4 is an enzyme that metabolizes D2HG in the β-oxygenation pathway and its mutation has been reported to cause hereditary peroxisomal disorders (20). Therefore the IDH enzymes together with HCDH4 affecting the prognosis of patients with CRC adds further support that D2HG is likely to play a role.…”

Section: Discussionmentioning

confidence: 97%

“…By using this approach, we identified 43 and 44 genes that had a significant effect on the DFS and OS, respectively (Table I). Of these ZNF91 (18,19) and HCDH4 [protein tyrosine phosphatase-like a domain containing 2 (PTPLAD2)] (20), were found to accentuate the reduction of both DFS and OS of CRC patients when IDH1 and IDH2 expression was imbalanced.…”

Section: Imbalance Between the Idh1 And Idh2 Expression Is Associatedmentioning

confidence: 99%

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Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

Koseki

Colvin

Fukusumi

et al. 2015

International Journal of Oncology

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Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer (CRC), and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in CRC patients. This effect was further accentuated by reduced expression of the β-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of CRC development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the β-oxidization pathway is diminished. Additional validation analysis with another gene expression dataset resulted in IDH1/2 imbalanced expression with a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of CRC.

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Section: Discussionmentioning

confidence: 97%

Section: Imbalance Between the Idh1 And Idh2 Expression Is Associatedmentioning

confidence: 99%

Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

Koseki

Colvin

Fukusumi

et al. 2015

International Journal of Oncology

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“…Also, of great interest is the fact that the majority (59%) of ZNFs identified from our siRNA screen are located within the 19p12–13.1 locus and belong to the ZNF 91 subfamily. 19p12–13.1 has recently been described as a breast and ovarian cancer susceptibility locus [40], [41], [42].…”

Section: Discussionmentioning

confidence: 99%

ZNF-Mediated Resistance to Imatinib Mesylate in Gastrointestinal Stromal Tumor

et al. 2013

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Although imatinib mesylate (IM) has transformed the treatment of gastrointestinal stromal tumors (GIST), many patients experience primary/secondary drug resistance. In a previous study, we identified a gene signature, consisting mainly of Kruppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors that predict short-term response to IM. To determine if these genes have functional significance, a siRNA library targeting these genes was constructed and applied to GIST cells in vitro. These screens identified seventeen “IM sensitizing genes” in GIST cells (sensitization index (SI) <0.85 ratio of drug/vehicle) with a false discovery rate (FDR) <15%, including twelve ZNF genes, the majority of which are located within the HSA19p12–13.1 locus. These genes were shown to be highly specific to IM and another tyrosine kinase inhibitor (TKI), sunitinib, in GIST cells. In order to determine mechanistically how these ZNFs might be modulating response to IM, RNAi approaches were used to individually silence genes within the predictive signature in GIST cells and expression profiling was performed. Knockdown of the 14 IM-sensitizing genes (10 ZNFs) universally led to downregulation of six genes, including TGFb3, periostin, and NEDD9. These studies implicate a role of KRAB-ZNFs in modulating response to TKIs in GIST.

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“…Data from the aCGH analysis were originally annotated according to the Human Genome 18 (hg18) NCBI36 (Micci et al, ). To enable integration of the two data sets, the aCGH data were converted to the Human Genome 19 (hg19) GRCh37 using the LiftOver tool at UCSC (http://genome.ucsc.edu/cgi-bin/hgLiftOver).…”

Section: Methodsmentioning

confidence: 99%

“…A total of 24 of the 39 (62%) genes showing association between expression and gain in at least two samples belong to the zinc finger gene family ( Table 2). The zinc finger (ZNF) genes with Samples with DNA gain in gene locus identified by aCGH (Micci et al, 2010).…”

Section: Overrepresentation Of the Zinc Finger Gene Familymentioning

confidence: 99%

Chromosome 19 rearrangements in ovarian carcinomas: Zinc finger genes are particularly targeted

Smebye

Sveen

Haugom

et al. 2014

Genes Chromosomes & Cancer

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Chromosome 19 is frequently rearranged in ovarian carcinomas, but the pathogenetic consequences of this are not clearly understood. We performed microarray gene expression analysis on 12 ovarian carcinomas that carry a rearranged chromosome 19 in their karyotype. These aberrant chromosomes have previously been microdissected and analyzed by array-based CGH. In the current study, we wanted to explore whether the genomic alterations thus detected correlated with changes in gene expression. The microarray gene expression analysis gave information on 407 genes mapping in gained genomic regions on chromosome 19, of which 92 showed association between DNA gain and upregulated expression. Of the genes showing this association, 39 (42%) showed gain in at least two samples. The majority of these 39 genes of interest (n = 24, 62%) encode zinc finger proteins, which otherwise make up only 15% of the approximately 1,400 genes on chromosome 19. The strongest association was found for ZNF223 which was upregulated in samples with genomic gain compared with samples without gain. We suggest that DNA copy number changes brought about by rearrangements of chromosome 19 contribute to ovarian carcinogenesis by leading to upregulation of ZNF223 and other zinc finger genes. © 2014 Wiley Periodicals, Inc.

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Array‐CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes

Cited by 21 publications

References 17 publications

Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

ZNF-Mediated Resistance to Imatinib Mesylate in Gastrointestinal Stromal Tumor

Chromosome 19 rearrangements in ovarian carcinomas: Zinc finger genes are particularly targeted

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