Interaction of PAX2 and PTEN Drives Emergence of Endometrial Precancers from a Preclinical Latent Phase
GL Mutter, NM Monte, KA Webster, D Neuberg, GR Dressler. Brigham and Women's Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Univ. Michigan, Ann Arbor, MI
Background: Latent endometrial precancers are small numbers of normal appearing glands with sporadic inactivation of tumor suppressor genes such as PTEN. These advance to cancer at low efficiency only upon acquisition of additional genetic damage. We here present evidence that inactivation of the transcription factor PAX2, which is required for embryonic development of a uterus, behaves as a latent precancer, and study its association with PTEN during endometrial carcinogenesis.
Design: Normal (premenopausal proliferative n=191), premalignant (EIN, n=52), and malignant (endometrial adenocarcinoma, n=62) endometrial biopsy and curetting tissues were immunostained for PTEN and PAX2. Proliferative samples with discrete loss of PAX2 or PTEN protein in at least one gland were scored as latent precancers, and the number of affected glands counted. EIN and cancer lesions were scored overall. Latent precancer prevalence and number of affected proliferative glands was analyzed by biopsy indication and age. Overlapping PAX2 and PTEN co-inactivation was examined in each tissue type.
Results: The prevalence of PAX2 inactivation in the sequence of normal (latent precancer) to EIN to cancer was 36%, 71%, and 77% respectively, and for PTEN 49%, 44%, and 68%. Amongst normal proliferative endometria, the prevalence of both PAX2 and PTEN defined latent precancers was unaffected by biopsy indication but increased significantly with age. Coincident inactivation of PAX2 and PTEN in an individual normal endometrium was seen in 21% (40) of patients, but these usually involved different subsets of glands. Of a total of 1281 null glands (449 PAX2 null and 847 PTEN null) seen in these 40 patients, only 15 individual glands (1.2%) had inactivation of both. Coincident inactivation was more common in EIN (31%) and carcinoma (55%), with both genes co-inactivated in the majority (>90%) of glands.
Conclusions: PAX2 and PTEN are biomarkers for latent precancers which accumulate independently with increasing age in normal premenopausal endometrium. Independent inactivation of either may occur in normal tissues, whereas inactivation of both genes in an overlapping distribution characterizes premalignant EIN lesions and carcinoma. This suggests that PAX2 acts as a tumor suppressor in the endometrium, but other events such as PTEN inactivation are required to develop clinical disease.
Category: Gynecologic & Obstetrics
Monday, March 22, 2010 1:15 PM
Platform Session: Section C, Monday Afternoon