Amplification and overexpression of the <i>IGF2</i> regulator <i>PLAG1</i> in hepatoblastoma

Zaťková, Andrea; Rouillard, Jean Marie; Hartmann, Wolfgang; Lamb, Barbara; Kuick, Rork; Eckart, Markus; Schweinitz, Dietrich von; Koch, Arend; Fonatsch, Christa; Pietsch, Torsten; Hanash, Sam; Wimmer, Katharina

doi:10.1002/gcc.10307

Cited by 114 publications

(96 citation statements)

References 34 publications

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“…In this study, HB tumours with PLAG1 mRNA expression showed and tended to show higher levels of P4 and P3 transcripts, respectively. Thus, the correlation of PLAG1 mRNA expression with increased levels of P3 transcripts reported by Zatkova et al (2004) may be confirmed; furthermore, the correlation of PLAG1 mRNA expression with increased levels of P4 transcripts was also suggested.…”

Section: Loss Of Imprinting Ofmentioning

confidence: 63%

“…PLAG1 located in 8q11 encodes a developmentally regulated transcription factor, and positively regulates IGF2. The P3 promoter region of IGF2 contains PLAG1 consensus-binding sites, and PLAG1 transactivates the transcription from embryonic IGF2 promoter P3 in HB cell lines, HuH6 and HepG2 (Zatkova et al, 2004). PLAG1 mRNA was highly expressed in most HB tumours compared with normal liver tissues.…”

Section: Loss Of Imprinting Ofmentioning

confidence: 97%

“…The primer sequences for P2-specific transcript were derived from exons 4 and 5: forward, 5 0 -CCCTCAGGACGTGGACAG-3 0 ; reverse, 5 0 -GTGCGTTGGACTTGCATAGA-3 0 ; and the primer sequences for P4-specific transcript were derived from exons 7, 8 and 9: forward, 5 0 -CGAGCCTTCTGCTGAGCTAC-3 0 ; reverse, 5 0 -CGGAAACAGCA CTCCTCAAC-3 0 . PLAG1 mRNA expression was analysed using the following primer sets: forward, 5 0 -AACGTAAGCGTGGTGAAACC-3 0 ; reverse, 5 0 -TGCCACATTCTTCGCACTTA-3 0 (Zatkova et al, 2004). Polymerase chain reaction products were run on polyacrylamide gels and visualised after ethidium bromide staining.…”

Section: Loh Analysis Of Igf2mentioning

confidence: 99%

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Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma

Honda

Arai²,

Haruta

et al. 2008

Br J Cancer

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IGF2, a maternally imprinted foetal growth factor gene, is implicated in many childhood tumours including hepatoblastoma (HB); however, the genetic and epigenetic alterations have not comprehensively been studied. We analysed the methylation status of the H19 differentially methylated region (DMR), loss of heterozygosity (LOH) and allelic expression of IGF2 in 54 HB tumours, and found that 12 tumours (22%) with LOH, 9 (17%) with loss of imprinting (LOI) and 33 (61%) with retention of imprinting (ROI). Biallelic and monoallelic IGF2 expressions correlated with hypermethylation and normal methylation of H19 DMR, respectively, in two tumours with LOI and seven tumours with ROI. Quantitative RT -PCR analysis showed minimal expression of H19 mRNA and substantial expression of IGF2 mRNA in tumours with LOH or LOI, and substantial expression of both H19 and IGF2 mRNAs in tumours with ROI. Increased IGF2 expression with predominant embryonic P3 transcript was found in the majority of HBs with ROI and foetal livers. In contrast to the earlier reports, our findings suggest that the disruption of the enhancer competition model reported in Wilms' tumour may also occur in HB. Both frequencies of LOH and LOI seem to be lower in HB than in Wilms' tumour, reflecting the different tissue origins.

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Section: Loss Of Imprinting Ofmentioning

confidence: 63%

Section: Loss Of Imprinting Ofmentioning

confidence: 97%

Section: Loh Analysis Of Igf2mentioning

confidence: 99%

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Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma

Honda

Arai²,

Haruta

et al. 2008

Br J Cancer

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“…PLAG1 encodes for a transcription factor whose ectopic expression can trigger the development of several benign mesenchymal tumors (41). Indeed, the overexpression of PLAG1 is typically triggered by chromosomal translocations or, in rarer cases, by amplifications (42). PLAG1 and HMGA2 translocations are both frequent and mutually exclusive in pleomorphic adenomas of the salivary gland (43).…”

Section: Discussionmentioning

confidence: 99%

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

Mehine

Kaasinen

Heinonen

et al. 2016

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

190

231

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Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/β-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.uterine leiomyoma | transcriptional profiling | MED12 | HMGA2

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“…Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of lipoblastomas and pleomorphic adenomas of the salivary gland (Hensen et al, 2002;Voz et al, 2004;Zatkova et al, 2004) (GeneCards GCID:GC08M057073 (http://www.genecards.org/cgibin/carddisp.pl?gene=PLAG1), UniProt Q6DJT9-PLAG1_HUMAN (http://www.uniprot.org/uniprot/Q6DJT9)).…”

Section: Plag1mentioning

confidence: 99%