Abstract 104: PAX2 dysregulation in the fallopian tube and pelvic serous cancer

Abstract

Abstract High grade ovarian serous cancer in women has been linked to the distal fallopian tube via a carcinogenic sequence of p53 mutations in both a clonally-derived precursor (p53 signature) and an early malignancy (tubal intraepithelial carcinoma)(Lee 2007). Dysregulation of additional genes, including PTEN and PAX2, has been associated with this early carcinogenic sequence and advanced ovarian serous cancers. Dysregulation of PAX2 has not been linked to genetic mutations, and has been recently documented throughout the tube within discrete secretory cell outgrowths (SCOUTs), particularly in fallopian tubes of women with serous cancer (Chen 2010). This study explored the frequency of PAX2-null SCOUTs in the fallopian tube and other potential molecular and cell kinetic correlates of this phenomenon. Fallopian tubes from a wide range of subjects, including (1) pre-adolescents (n=20), women undergoing (2) post-partum tubal ligation (n=25), (3) salpingectomy during surgery for benign disease (n=20), surgery for (4) endometriosis (n=47), (5) low grade endometrioid adenocarcinomas of the ovary (n=42), and (6) high-grade ovarian serous carcinomas (n=12) were immunostained and scored blindly for PAX2-null SCOUTs. Extracted tubal DNA from cancers and controls was analyzed for hypermethylation of the PAX2 promotor by real-time PCR and fallopian tube epithelial cultures were established from cancers and controls to assess clonogenic capacity. Review of over 350 tissue blocks revealed a frequency (%) of PAX2-null SCOUTs of 0, 0.5, 11, 5, 4.5 and 56.2 for groups 1-6 above, respectively, yielding a 5-50-fold increase in the tubes of patients with serous cancer (p < .001). A preliminary analysis of DNA from one cancer-associated fallopian tube revealed a relative increase in PAX2 promotor methylation. A striking increase in cell growth (clonogenic) capacity was observed in tubes from cancer patients versus controls. This study reveals, for the first time, that functional loss of PAX2 expression is linked to a morphologically defined entity (SCOUT) in the fallopian tube that is absent in pre-adolescent fallopian tubes and post-partum tubal ligations, increases with age, and is exquisitely linked to co-existing high grade ovarian serous carcinoma. This unique dysregulation of PAX2 appears to segregate with a markedly higher in vitro clonogenic potential of tubal epithelium in women with serous cancer. The potential that this highly prevalent entity (PAX2-null SCOUT) and its milieu in fallopian tube epithelium of women with serous cancer can be exploited as a predictor of concurrent or future ovarian serous carcinoma is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2011-104