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

BJC reports Pub Date : 2025-02-27 DOI:10.1038/s44276-025-00127-4

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

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Abstract

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.

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子宫平滑肌瘤中基因和表观遗传改变对FGFR基因激活的影响。

背景：成纤维细胞生长因子1-4 （FGFR1-4）是许多癌症类型中众所周知的致癌驱动因子。在这里，我们研究了fgfr在子宫平滑肌瘤（UL）中的作用，子宫平滑肌瘤是一种起源于子宫肌层的良性肿瘤，也是女性中最常见的肿瘤。虽然ULs可以根据遗传驱动因素分类为分子亚型，但潜在的次要驱动因素尚未得到很好的表征。方法：我们对ULs的rna测序数据进行突变分析，然后利用Sanger-，下一代和纳米孔测序和SNP阵列数据，筛选芬兰（n = 2677）和瑞典（n = 372） UL收集的FGFR改变。GWAS检测了FGFR基因在UL易感性中的作用。结果：我们在遗传和表观遗传水平上确定了ULs子集中FGFR的激活。除了FGFR1/2中的单核苷酸突变外，我们还检测到FGFR2-ERC1融合基因，FGFR1获得和FGFR2/3调控区域的低甲基化。FGFR改变富集在分子相似的HMGA2、HMGA1和PLAG1 UL亚型中。我们还揭示了FGFR4上游与正常肌层和ULs中表达增加相关的UL易感变异。结论：我们的研究结果确定了FGFR信号在UL发生中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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