title: Oviduct-specific glycoprotein is a molecular marker for invasion in endometrial tumorigenesis identified using a relevant mouse model.
abstract: The light microscopic distinction between complex atypical hyperplasia (CAH) and invasive endometrioid carcinoma (UEC) on endometrial sampling is problematic and often has significant clinical implications. Using mouse models of endometrial tumorigenesis based on two of the most common molecular alterations found in primary human UEC we sought to characterize the transition from CAH to carcinoma to identify clinically useful biomarkers. We used the previously described Pten(+/-); Mlh1(-/-) mouse model. DNA was isolated from microdissected lesions (CAH and carcinoma) and analyzed for LOH and mutations of Pten and additional candidate genes. To identify novel candidate genes associated with invasion, global gene expression profiles were compared from uteri with extensive CAH and carcinoma. The majority of CAHs and carcinomas, arising in this model showed biallelic inactivation of Pten mediated through LOH or intragenic mutation of the wild-type allele suggesting that complete loss of Pten is insufficient for the development of carcinoma. The global gene expression studies detected increased expression of oviduct-specific glycoprotein (OGP) in carcinoma as compared with CAHs. This finding was validated using immunohistochemical staining in a collection of primary human UECs and CAHs. Our studies identify a molecular marker for invasive endometrial cancer that may have clinical significance, and highlight the usefulness of this mouse model in not only understanding the genetic underpinnings of endometrial carcinoma, but as a tool to develop clinically relevant biomarkers.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Ayesha
authors.initials: A
authors.lastname: Joshi
authors.forename: Lori
authors.initials: L
authors.lastname: Iaconis
authors.forename: Garron J
authors.initials: GJ
authors.lastname: Solomon
authors.forename: Zhaoying
authors.initials: Z
authors.lastname: Xiang
authors.forename: Harold G
authors.initials: HG
authors.lastname: Verhage
authors.forename: Wayne
authors.initials: W
authors.lastname: Douglas
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Ronnett
authors.forename: Lora Hedrick
authors.initials: LH
authors.lastname: Ellenson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000473:pathology*; D005091:Exons; D005187:Fallopian Tubes / Q000473:pathology*; D005260:Female; D005838:Genotype; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D017931:DNA Primers; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000070957:MutL Protein Homolog 1