title: High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression.
abstract: High-grade endometrioid and serous carcinomas of the ovary and fallopian tube are responsible for the majority of cancer deaths and comprise a spectrum that includes early or localized (tubal intraepithelial carcinoma) and advanced (invasive or metastatic) disease. We subdivided a series of these tumors into three groups, (1) classic serous, (2) mixed serous and endometrioid and (3) endometrioid carcinomas and determined: (1) the frequencies of coexisting tubal intraepithelial carcinoma, (2) frequency of a dominant ovarian mass suggesting an ovarian origin and (3) immuno-localization of WT-1, p53, PTEN, PAX2 and p16(ink4). All tumors were analyzed for p53 mutations. Thirty six, 25 and 8% of groups 1-3 were associated with tubal intraepithelial carcinoma (P=0.09) and 34, 45 and 62% predominated in one ovary (P=0.028), respectively. Differences in frequencies of diffuse p53 immunostaining (85-93%), WT-1 (70-98%) and p16(ink4) positivity (69-75%) were not significant for all groups. Greater than 95% reduction in PAX2 and PTEN occurred in 67-75 and 5-12%, respectively; however, PAX2 and PTEN staining intensity, when present, was often heterogeneous, highlighting different tumor populations. PAX2 and PTEN expression were markedly reduced or absent in 12 of 12 and 4 of 12 tubal intraepithelial carcinomas. In summary, high-grade müllerian carcinomas share identical frequencies of altered or reduced expression of p53, PTEN and PAX2, all of which can be appreciated in tubal intraepithelial carcinomas. Because only a subset of these tumors appears to arise in the fallopian tube, attention to expression of these biomarkers in the ovary and other müllerian sites might facilitate the identification of other carcinogenic pathways. PAX2 and PTEN, in addition to p53 and p16(ink4), comprise a potentially important gene combination in high-grade pelvic carcinogenesis.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Roh
authors.forename: Yosuf
authors.initials: Y
authors.lastname: Yassin
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Karishma K
authors.initials: KK
authors.lastname: Mehra
authors.forename: Mitra
authors.initials: M
authors.lastname: Mehrad
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Monte
authors.forename: George L
authors.initials: GL
authors.lastname: Mutter
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
authors.forename: Geng
authors.initials: G
authors.lastname: Ning
authors.forename: Frank D
authors.initials: FD
authors.lastname: Mckeon
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.forename: Xian
authors.initials: X
authors.lastname: Wa
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005185:Fallopian Tube Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051762:PAX2 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human