The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

Abstract

Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7p/PAX2n/EZH2pand underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2pbut became PAX2nin multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2nSCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1nand β-cateninmem(membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc(nuclear and cytoplasmic), stathminp, LEF1p, RCN1p, and RUNX2pexpression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2nwith proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.