Aggressive Serous Carcinomas of the Female Reproductive Tract: Cancer-Prone Cell States and Genetic Drivers

Abstract

In 2025, gynecological cancers are projected to account for approximately 10% of cancer-related deaths in women. High-grade serous ovarian carcinoma (HGSC) and serous endometrial carcinoma (SEC) are the most lethal gynecological cancer subtypes. Both malignancies commonly have TP53 mutations, alterations of the RB1 pathway, and numerous secondary mutations. Both carcinoma types consist of poorly differentiated and highly heterogeneous cell populations at the time of detection. Latent development and rapid progression of HGSC and SEC impede the identification of definitive cells of origin and genetic drivers. Here, we review our current knowledge about cancer-prone cell states and genetic drivers. We also discuss how emerging transcriptomic and genetic tools applied to contemporary model systems may facilitate the identification of novel targets for timely detection and therapeutic intervention.

Keywords: cancer-prone cell state; genetic drivers; ovarian cancer; uterine cancer.

Figure 1

Cancer-prone cell states of the mouse ovarian surface epithelium (OSE) and distal tubal epithelium (DTE). (A) The differentiation trajectory of Lgr5⁺, ALDH1⁺ stem/progenitor cells for the (OSE) begins in the hilum and encompasses the whole OSE. Inactivation of Trp53 and Rb1 in Lgr5⁺ cells leads to high-grade serous carcinoma (HGSC). (B) The DTE has Slc1a3⁺ stem/progenitor cells that give rise to secretory (Upk1a⁺) and ciliated (Fam183b⁺) cell lineages. Slc1a3⁺ stem/progenitor cells do not transform and undergo apoptosis, while Krt5⁺ pre-ciliated cells do initiate HGSC after inactivation of Trp53 and Rb1.

Figure 2

Cell composition of the mouse endometrial epithelium. Putative cancer-prone sites include luminal epithelium (LE; blue, columnar cells), transition zone (purple cells), and glandular epithelium (GE; red, cuboidal cells). The inactivation of Trp53 and Rb1 in Pax8⁺ cells results in serous endometrial carcinoma (SEC). Pax8 is expressed in both the LE and GE. It plays a critical role in the development of Müllerian duct-derived tissues, such as the uterus and uterine tube. The glandular epithelium contains Axin2⁺ cells, which are needed for proper glandular development. When an oncogenic form of Pik3ca and overexpression of Ctnnb1 are introduced to these cells, endometrial carcinoma (EC) of an unspecified subtype develops.

Figure 3

Comparison of genetically altered gene frequency between high-grade serous carcinoma (HGSC) and serous endometrial carcinoma (SEC). Genetic alterations are defined as gene mutations, amplifications, and deep deletion events. A total of 316 HGSC [33] samples and 44 SEC [68] samples were analyzed (TCGA datasets extracted via the cBioPortal interface) and plotted on a logarithmic scale. Note lack of MDM2, CDK4, BRCA1, and BRCA2 alterations in SEC.