Genetic and Molecular Studies of Endometrial Cancer

Endometrial cancer, which develops from the inner lining of the uterus, is the most common cancer of the female reproductive tract. Endometrial cancer is comprised of two epidemiologic, molecularly and genetically different subtypes known as type I and type II. Because of its clinical significance and aggressive behavior, my research focused on type II endometrial cancer. Type II endometrial cancer is associated with advanced age and TP53 mutations, which suggests a link between telomeres and the development of type II tumors. Telomeres and other markers of telomere status in type I and type II tumors were analyzed, short telomeres are observed in both tumor types. However, only type II tumors are associated with critical telomere shortening in the adjacent, morphologically normal epithelium. This suggests that telomere shortening contributes to the initiation of type II, but not of type I tumors. To further explore this hypothesis, 5th generation telomerase knockout mice with critically short telomeres were analyzed and a distinctive endometrial lesion that resembles the in situ precursor of type II carcinomas, endometrial intraepithelial carcinomas were observed. Subsequently, the role of dysfunctional telomeres in endometrial cancer development was investigated in the mouse by conditionally inactivating Pot1a, a key component of the shelterin complex that stabilizes telomeres in endometrial epithelium. Inactivation of Pot1a by itself does not stimulate endometrial carcinogenesis. However, simultaneous inactivation of Pot1a and p53 results in endometrial intraepithelial carcinoma-like lesions by 9 months and metastatic tumors in 100% of the animals by 15 months. These tumors are poorly differentiated endometrial carcinomas with prominent nuclear atypia, DNA damage, and aneuploidy, resembling human type II tumors. These studies thus lend support to the hypothesis that dysfunctional telomeres play a critical role in type II endometrial carcinogenesis.