Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review

Arslan, Alan A.; Gold, Leslie I.; Mittal, Khushbakhat; Suen, Ting-Chung; Belitskaya-Lévy, Ilana; Tang, Moon-shong; Toniolo, Paolo

doi:10.1093/humrep/deh698

Cited by 171 publications

(152 citation statements)

References 88 publications

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“…Compatible with previous expression profiling studies (14), our pathway analysis revealed a significant dysregulation of IGF1 signaling in leiomyomas. After HMGA2 itself, our statistical analysis identified IGF2BP2 as the second-most uniquely expressed gene in leiomyomas of the HMGA2 subtype.…”

Section: Discussionsupporting

confidence: 79%

“…Previous expression profiling studies have discovered that hundreds of genes are differentially expressed between leiomyomas and normal myometrial tissue (9,(14)(15)(16)(17)(18)(19)(20); however, the majority of these studies have not accounted for the genetic background of the lesions examined. Therefore, we sought to explore the transcriptional differences and similarities among 94 leiomyomas from 60 patients harboring different genetic driver alterations, including HMGA2 rearrangements, MED12 mutations, biallelic inactivation of FH, COL4A5-COL4A6…”

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confidence: 99%

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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.

187

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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Section: Discussionsupporting

confidence: 79%

mentioning

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.

187

231

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“…Although a number of studies have shown versican to be up-regulated in various types of cancers and versican levels have been shown to be altered in leiomyoma (18) (the benign neoplastic counterpart to LMS), only a limited number of studies have shown a differential regulation of versican in LMS (19,20). To further examine the involvement of versican in LMS, we analyzed 12 LMS and three leiomyoma clinical samples by immunohistochemistry and 80 LMSs and 24 leiomyomas by microarray to compare versican expression levels in these malignant versus benign neoplasms.…”

Section: Leiomyosarcoma (Lms)mentioning

confidence: 99%

A Role for Versican in the Development of Leiomyosarcoma

Keire

Bressler

Lemire

et al. 2014

Journal of Biological Chemistry

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“…Currently, uterine fibroids are the single-most common reason for hysterectomy in developed countries (Treloar et al 1999, Farquhar & Steiner 2002, Garry 2005, and despite their large healthcare burden, there is limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Gene profiling studies by our laboratory and others have identified a large number of genes with altered expression in fibroid tumours compared with myometrium (Tsibris et al 2002, Skubitz & Skubitz 2003, Arslan et al 2005, Luo et al 2005a, 2005b, Zaitseva et al 2006, Dimitrova et al 2009). However, it is hypothesised that the majority of these genes are differentially expressed as a consequence of the changed microenvironment caused by the fibroids' presence and are not causal to fibroid development.…”

Section: Introductionmentioning

confidence: 97%

“…RA has implications in uterine fibroid pathology (Arslan et al 2005, Zaitseva et al 2007, and CTNNB1 is a RA-responsive gene (Byers et al 1996). By interacting with RA receptor (RAR) and retinoid X receptor (RXR), NR2F2 negatively regulates RA signalling (reviewed by Boudot et al (2011)).…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

Zaitseva¹,

Holdsworth-Carson²,

Waldrip³

et al. 2013

Reproduction

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Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures.In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.

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Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review

Abstract: Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis, IGF metabolism, TGF-beta signaling and extracellular matrix formation. Gene expression studies provide clues to the relevant pathways of leiomyoma development.

Cited by 171 publications

References 88 publications

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

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

A Role for Versican in the Development of Leiomyosarcoma

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

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