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Background <p><i>Fibroblast growth factor 1-4 (FGFR1-4)</i> are well-known oncogenic drivers in many cancer types. Here, we studied the role of FGFRs in uterine leiomyoma (UL) that is a benign neoplasm arising from the myometrium and the most common tumour in women. Although ULs can be classified to molecular subtypes based on genetic drivers, potential secondary drivers are not well characterised.</p> Methods <p>We performed mutation analysis of RNA-sequencing data of ULs, followed by screening of <i>FGFR</i> alterations in our Finnish (<i>n</i> = 2677) and Swedish (<i>n</i> = 372) UL collections, utilising Sanger-, next-generation and Nanopore sequencing and SNP array data. The role of <i>FGFR</i> genes in UL predisposition was examined by GWAS.</p> Results <p>We identified FGFR activation in a subset of ULs on both genetic and epigenetic levels. In addition to single-nucleotide mutations in <i>FGFR1/2</i>, we detected an <i>FGFR2-ERC1</i> fusion gene, <i>FGFR1</i> gains and hypomethylation of regulatory regions of <i>FGFR2/3</i>. <i>FGFR</i> alterations were enriched in molecularly similar HMGA2, HMGA1 and PLAG1 UL subtypes. We also unveil a UL predisposing variant upstream of <i>FGFR4</i> associated with increased expression in both normal myometrium and ULs.</p> Conclusions <p>Our results establish the role of FGFR signalling in the genesis of UL.</p>

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Activation of FGFR genes by genetic and epigenetic alterations in uterine leiomyomas

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  • 发表日期：

    2025年2月27日

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  • Vilja Jokinen,
  • Aurora Taira,
  • Åsa Kolterud,
  • Isa Ahlgren,
  • Kimmo Palin,
  • Riku Katainen,
  • Maritta Räisänen,
  • Eevi Kaasinen,
  • Sini Ilves,
  • Anniina Raitila,
  • Helena Kopp Kallner,
  • Emma Siili,
  • Ralf Bützow,
  • Oskari Heikinheimo,
  • Annukka Pasanen,
  • Auli Karhu,
  • Niko Välimäki,
  • Lauri A. Aaltonen

摘要

Background

Fibroblast growth factor 1-4 (FGFR1-4) are well-known oncogenic drivers in many cancer types. Here, we studied the role of FGFRs in uterine leiomyoma (UL) that is a benign neoplasm arising from the myometrium and the most common tumour in women. Although ULs can be classified to molecular subtypes based on genetic drivers, potential secondary drivers are not well characterised.

Methods

We performed mutation analysis of RNA-sequencing data of ULs, followed by screening of FGFR alterations in our Finnish (n = 2677) and Swedish (n = 372) UL collections, utilising Sanger-, next-generation and Nanopore sequencing and SNP array data. The role of FGFR genes in UL predisposition was examined by GWAS.

Results

We identified FGFR activation in a subset of ULs on both genetic and epigenetic levels. In addition to single-nucleotide mutations in FGFR1/2, we detected an FGFR2-ERC1 fusion gene, FGFR1 gains and hypomethylation of regulatory regions of FGFR2/3. FGFR alterations were enriched in molecularly similar HMGA2, HMGA1 and PLAG1 UL subtypes. We also unveil a UL predisposing variant upstream of FGFR4 associated with increased expression in both normal myometrium and ULs.

Conclusions

Our results establish the role of FGFR signalling in the genesis of UL.