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Originally published online as doi:10.2353/ajpath.2008.071179 on July 3, 2008

Published online before print July 3, 2008
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(American Journal of Pathology. 2008;173:536-544.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071179

Differential Roles of Telomere Attrition in Type I and II Endometrial Carcinogenesis

Esra A. Akbay*{dagger}, Cristina M. Contreras*{dagger}, Samanthi A. Perera{ddagger}, James P. Sullivan{dagger}§, Russell R. Broaddus, John O. Schorge{dagger}§||, Raheela Ashfaq*{dagger}, Hossein Saboorian**, Kwok-Kin Wong{ddagger} and Diego H. Castrillon*{dagger}

From the Department of Pathology,* Simmons Comprehensive Cancer Center,{dagger} Hamon Center for Therapeutic Oncology Research,§ and the Department of Obstetrics and Gynecology,|| Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; the Department of Pathology, MD Anderson Cancer Center, Houston, Texas; the Department of Medical Oncology,{ddagger} Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and Caris Diagnostics,** Irving, Texas

Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers.






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