Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

Hiroshi Kobayashi
In: World Academy of Sciences Journal · 2019 · doi:10.3892/wasj.2019.12 · W2944474914
article OA: diamond CC0 ⤵ 2 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This review assesses how somatic driver gene mutations in endometriosis, driven by oxidative stress, may promote fibrogenesis and potentially serve as a precursor to certain cancers in organs like the liver, kidney, and lung.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This review investigated whether somatic driver mutations reported in endometriosis could regulate fibrogenesis by synthesizing literature on associations between endometriosis-susceptibility driver gene mutations and fibrosis-related gene alterations in the liver, kidney, and lung, using a PubMed/Embase search through December 2018. It proposes a mechanism in which repeated hemorrhage–driven oxidative stress and (epi)genetic DNA damage in endometriotic tissue leads to driver mutations that promote epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and fibrogenic signaling (notably TGF-β/Smad), culminating in α-SMA and collagen production and ultimately fibrosis, with a possible sequential path toward low-grade pre-neoplasia and carcinogenesis. A major limitation is that the review states there are no studies directly showing whether these mutated driver genes are required for development of endometriosis-related fibrosis. This paper is centrally about endometriosis — it reviews somatic driver mutations in endometriosis and how they may regulate fibrogenic processes.

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Abstract

The aim of this review article was to assess the potential link between somatic driver mutations in endometriosis and the pathogenesis of fibrotic processes in other organ systems. This review presents the results of a PubMed literature search for publications dealing with the association between the endometriosis susceptibility driver gene mutations and pathological gene alterations related to fibrosis in the liver, kidney and lung. Genetic studies have demonstrated that endometriosis has somatic mutations in driver genes, including AT-rich interaction domain 1A (ARID1A), phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), KRAS, tumor protein P53 (TP53), P16 or B-Raf proto-oncogene, serine/threonine kinase (BRAF), directly related to neoplasms. Tissue injury and repair induce inflammation and oxidative stress, which induces (epi)genetic DNA damage and mutations, promotes epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) through the induction of fibrogenic signaling pathways regulated by transforming growth factor (TGF)-β/Smad and these driver genes, resulting in α-smooth muscle actin (α-SMA) and collagen production and increased cellular contractility, leading to increased smooth muscle metaplasia (SMM) and fibrosis. Elevated levels of reactive oxygen species may lead to increased damage to DNA and may induce cell cycle arrest accompanied by the acquisition of replication stress, senescence-associated characteristics and carcinogenesis, at least to a certain extent. This process may be a major hallmark of fibrogenesis of the liver, kidney and lung. Given that somatic driver mutations occur frequently in benign endometriosis and the physiologically normal endometrium, there may be at least 2 distinct phases of epigenetic and genetic modifications in endometriosis: The initial wave of hemoglobin-induced oxidative stress and (epi)genetic DNA damages and mutations would be followed by the second big wave of cellular senescence, fibrogenesis and finally, carcinogenesis. Thus, it can be concluded that endometriosis may represent a hemorrhage-induced fibrotic and low-grade pre-neoplastic lesion that may be a precursor lesion of a subset of malignant transformation.

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endometriosis

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