Genetic markers of endometrial hyperplasia: from pathogenesis to personalized therapy

Endometrial hyperplasia, particularly in perimenopause, constitutes a major clinical challenge in gynecology due to its high risk of malignant transformation into endometrial cancer, which is driven by a complex interplay between genetic alterations and hormonal imbalance. Evidence suggests that certain genetic markers (ESR1, C-MYC, PIK3CA, PTENP1, MTHFR, EGFR) contribute to the pathogenesis of endometrial hyperplasia by disrupting the regulation of proliferation, apoptosis, and DNA methylation. ESR1 polymorphisms increase estrogen receptor density, thereby enhancing the proliferative response of the endometrium. C-MYC overexpression correlates with progression to atypical forms, although it is also observed during physiologic regeneration. PIK3CA mutations result in constitutive activation of the PI3K/AKT/mTOR pathway and are associated with therapeutic resistance. Loss of function of the pseudogene PTENP1 disrupts regulation of the tumor suppressor PTEN, thereby promoting uncontrolled cellular proliferation. MTHFR polymorphisms impair DNA methylation and heighten susceptibility to epigenetic dysregulation. EGFR overexpression enhances proliferation through the MAPK/ERK pathway, particularly in obesity. The clinical significance of these markers is often influenced by underlying conditions, and their role remains ambiguous due to population differences and methodological heterogeneity across studies. A promising direction in the management of this condition is the development of integrative prognostic models that combine genetic testing with clinical parameters for risk stratification and early prevention of endometrial cancer.