title: Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer.
abstract: Latent endometrial carcinoma precancers are normal-appearing endometrial glands with sporadic loss of tumor suppressor gene function such as PTEN. Progression to carcinoma is inefficient and requires additional genetic damage that creates a histologic precursor lesion called endometrial intraepithelial neoplasia (EIN). In this study, we examined loss of PAX2 expression, a gene required for embryonic uterine development, during endometrial carcinogenesis. Normal proliferative, EIN, and malignant (endometrial adenocarcinoma) endometrial tissues were immunostained for PTEN and PAX2. Proliferative samples with loss of protein in at least one gland were scored as latent precancers. EIN and cancer lesions were scored by the majority pattern. Overall prevalence and topography of joint PAX2-PTEN expression loss was examined. The prevalence of PAX2 protein loss in the sequence of normal to precancer to cancer was 36%, 71%, and 77%, respectively, and for PTEN, it was 49%, 44%, and 68%, respectively. The normal endometrial prevalence of PAX2- or PTEN-deficient latent precancers was unaffected by biopsy indication, but increased significantly with age. Coincident loss of PAX2 and PTEN expression in an individual normal endometrium was seen in 21% of patients, but usually involved different glands. Coincident loss was more common in precancers (31%) and carcinoma (55%), in which case, both markers were protein null in an overlapping clonal distribution. PAX2 and PTEN protein loss occurs independently and accumulates with increasing age in latent precancers of normal premenopausal endometrium. Loss of function of both genes in an overlapping distribution characterizes the clinical emergence of a premalignant lesion which is carried forward to carcinoma.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Monte
authors.forename: Kaitlyn A
authors.initials: KA
authors.lastname: Webster
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Dressler
authors.forename: George L
authors.initials: GL
authors.lastname: Mutter
mesh_terms: D000328:Adult; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D051762:PAX2 Transcription Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human