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<p>High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive subtype among ovarian cancers and is associated with poor prognosis. The molecular mechanism of HGSOC development and metastasis is complex and associated with genomic instability due to abnormal DNA repair systems. This leads to the loss of tumor suppressors and amplification of oncogenes that are accompanied by epigenetic alterations. Despite its name and complexity, there is debate about its origin; however, recent findings on genetic and epigenetic features in animal models and human samples suggest that fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) are the main origin sites of HGSOC development. Since OSE-derived tumors are associated with chemoresistance and poor survival rates, understanding HGSOC origin is clinically valuable for selecting appropriate treatment. This review focuses on the early genetic and epigenetic changes that characterize tumors originating from FTE versus OSE, highlighting how these differences may influence clinical behavior and treatment response. Uncovering the early molecular mechanisms that drive the distinct origins of HGSOC is essential for a deeper understanding of how this cancer develops. These insights could pave the way for the development of precise, biomarker-based strategies for early detection and more effective treatment. In line with this goal, the final section of our review highlights emerging non-invasive screening methods such as mutation and epigenetic profiling of circulating tumor DNA (ctDNA), along with transcriptomic analysis of microRNAs in body fluids. These emerging approaches show strong potential as biomarkers for early diagnosis and for predicting patients’ therapy response.</p> Graphical abstract <p>Studies using engineered animal models, organoids, and human patient samples suggest that high-grade serous ovarian cancer (HGSOC) originates from both the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE), each with distinct genetic and epigenetic mechanisms and clinical outcomes. Identifying the early molecular changes associated with each origin may facilitate the discovery of diagnostic and prognostic biomarkers for early-stage HGSOC screening.</p> <p></p>

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Distinct origins of high-grade serous ovarian carcinoma: genetic and epigenetic evidence linking ovarian and fallopian tube epithelium to clinical outcomes and early detection

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Mohammad Ghanbari,
  • Aida Aghazadeh,
  • Maitham Alhajamee,
  • Mohammed Ismael Ibrahim Jebur,
  • Dheyaa Obaid Alamara,
  • Mustafa Mutashar Ghalib,
  • Mehdi Haghi

摘要

High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive subtype among ovarian cancers and is associated with poor prognosis. The molecular mechanism of HGSOC development and metastasis is complex and associated with genomic instability due to abnormal DNA repair systems. This leads to the loss of tumor suppressors and amplification of oncogenes that are accompanied by epigenetic alterations. Despite its name and complexity, there is debate about its origin; however, recent findings on genetic and epigenetic features in animal models and human samples suggest that fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) are the main origin sites of HGSOC development. Since OSE-derived tumors are associated with chemoresistance and poor survival rates, understanding HGSOC origin is clinically valuable for selecting appropriate treatment. This review focuses on the early genetic and epigenetic changes that characterize tumors originating from FTE versus OSE, highlighting how these differences may influence clinical behavior and treatment response. Uncovering the early molecular mechanisms that drive the distinct origins of HGSOC is essential for a deeper understanding of how this cancer develops. These insights could pave the way for the development of precise, biomarker-based strategies for early detection and more effective treatment. In line with this goal, the final section of our review highlights emerging non-invasive screening methods such as mutation and epigenetic profiling of circulating tumor DNA (ctDNA), along with transcriptomic analysis of microRNAs in body fluids. These emerging approaches show strong potential as biomarkers for early diagnosis and for predicting patients’ therapy response.

Graphical abstract

Studies using engineered animal models, organoids, and human patient samples suggest that high-grade serous ovarian cancer (HGSOC) originates from both the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE), each with distinct genetic and epigenetic mechanisms and clinical outcomes. Identifying the early molecular changes associated with each origin may facilitate the discovery of diagnostic and prognostic biomarkers for early-stage HGSOC screening.