LINE-1 Deregulation in Ovarian Cancer: Implications for Diagnosis, Prognosis, and Therapeutic Targeting.

Ovarian cancer is a highly heterogeneous malignancy and remains a major cause of cancer-related mortality, mainly due to late diagnosis and frequent development of therapy resistance. Current diagnostic markers show limited sensitivity for early-stage disease, highlighting the need for novel biomarkers and improved understanding of tumor biology. Epigenetic deregulation is a hallmark of ovarian cancer, characterized by global DNA hypomethylation and focal hypermethylation of tumor suppressor genes. Among hypomethylated genomic regions, long interspersed nuclear elements-1 (LINE-1) represent a large fraction of the human genome and a widely used surrogate marker of global epigenetic instability. LINE-1 elements are normally epigenetically silenced. In ovarian cancer, loss of LINE-1 methylation leads to transcriptional reactivation, expression of ORF1p and ORF2p, and increased retrotransposition activity. These events contribute to genomic instability, DNA damage, insertional mutagenesis, tumor heterogeneity, and clonal evolution. LINE-1 deregulation is also associated with defects in DNA repair pathways, including homologous recombination deficiency, and may influence tumor progression and response to therapy. In addition, aberrant LINE-1 activity has been linked to activation of innate immune and interferon-related signaling pathways, supporting its biological relevance in cancer. Several studies indicate that LINE-1 hypomethylation is associated with aggressive tumor features and adverse clinical outcomes in ovarian cancer. Importantly, repetitive elements, including LINE-1, can be detected in circulating cell-free DNA (cfDNA), providing a technical basis for their evaluation as minimally invasive biomarkers. This review summarizes current knowledge on LINE-1 biology, epigenetic regulation, and functional consequences in ovarian cancer. In addition, we discuss the realistic potential of LINE-1 as a circulating epigenetic biomarker and therapeutic target.