Evidence That High-Grade Serous Cancers and Their Precursors Arise from a PAX2-Negative Progenitor Cell in the Oviduct
Gang Ning, Ju Yuan, Michael Herfs, Yasuke Yamamoto, Jonathan G Bijron, Frank D Mckeon, Wa Xian, Christopher P Crum. Jackson Laboratory for Genetic Medicine, Farmington, CT; Institute of Medical Biology, Singapore, Singapore; University of Liege, Liege, Belgium; Genome Insitute of Singapore, Singapore, Singapore; University of Utrecht, Utrechg, Netherlands; Brigham and Women's Hospital, Boston, MA
Background: Both a precursor (p53 signature) and early cancer (serous tubal intraepithelial carcinoma or STIC) have been linked to high-grade pelvic serous cancers (HGSC), both by p53 mutations and physical proximity in the fimbria. All strongly express PAX8, implying an origin in secretory-type cells of the tube. A number of other genes are up and down regulated in HGSC, including PAX2, which like PAX8, localizes to secretory cells. Absence or near loss of PAX2 expression (PAX2-) is seen in over 75% of HGSC. We hypothesized that absence of PAX2, rather than occurring during the development of precursors, might actually identify a population of precursor progenitor cells in the normal oviduct.
Design: We immunostained and compared oviductal epithelia stained with PAX8, a generic marker for secretory cells, and PAX2, to determine if PAX2 negative secretory cells existed. We next characterized a repository of precursors, including p53 signatures, atypias, STICs and other secretory cell outgrowths (SCOUTs) for loss of PAX2.
Results: Analysis of immunostains revealed discrete PAX2- cells in the oviducts, accounting for less than 10% of the resident secretory cell population. Immunostained sections of p53 signatures and STICs were typically PAX2-. PAX2- cell groups ranged from a few cells to over 30 (SCOUTs). Of the PAX2- SCOUTs, both pure secretory and mixed secretory and ciliated phenotypes were seen.
Conclusions: This report describes, for the first time, a specific candidate cell of origin for HGSC in the oviduct that is the PAX2- secretory cell. Based on their relative frequency, and proportion of precursors that are PAX2-, PAX2- cells appear to be particularly sensitive to clonal expansion. This population of PAX2- cells thus provides a unique substrate for studying cell-specific vulnerabilties in serous carcinogenesis as well as understanding the molecular underpinnings of the varied differentiation paths that seem to ensue during clonal expansion of this unique cell type.
Category: Gynecologic & Obstetrics
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 173, Wednesday Morning