Co-Ordinated Dysregulation of PAX2, ALDH1 and EZH2 in Tubal Serous Carcinogenesis.
Geng Ning, Anna R Laury, Charles M Quick, Michelle S Hirsch, Ronny Drapkin, Karishma K Mehra, Mitra Mehrad, Frank D McKeon, Christopher P Crum, Wa Xian. Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Saint Lukes Roosevelt Medical Center, New York, NY; Washington University, St. Louis, MO; A-Star Institute of Medical Biology, Singapore, Singapore
Background: The role of the fallopian tube in high-grade pelvic serous carcinoma (HGSCA) includes a benign precursor (p53 signature) with altered expression of p53, HMGA2 and PAX2. A second entity, secretory cell outgrowth (SCOUT), shares loss of PAX2 with p53 signatures and serous tubal intraepithelial carcinoma (STIC), which in turn have increased expression of Cyclin E, Ki-67, p16, FAS and RSF-1. This study expanded the list of genes altered in HGSCA development to more precisely define the components of this sequence.
Design: Whole-genome transcriptome analysis of laser micro-dissected paired cancer and tubal epithelium revealed loss of ALDH1 and upregulation of EZH2 (Xian unpublished). To determine their tissue specificity, tissue sections from HGSCA (n=16) and controls (n=65) were studied, and secretory cell outgrowths (SCOUTs; 30), p53 signatures (21), and STICS (33) were selectively stained with antibodies to p53, p16, PAX2, ALDH1 and EZH2.
Results: Fallopian tubes from HGSCA and controls averaged loss of PAX2 at frequencies of .56 and .11 per section respectively (p < .001). Coordinated loss of PAX2 and ALDH1 was seen in 70%; ALDH1 was also independently down-regulated in other SCOUTs. Concordant loss of PAX2 and ALDH1 was seen in 80% of p53 signatures exceeding 30-50 cells; expression was normal in very small p53 signatures (less than 20 cells). Loss of ALDH/PAX2 persisted in 80% of STICs but foci of staining were common in STICS and HGSCA. EZH2 stained scattered rare normal cells and a small number in SCOUTs and p53 signatures, and was increased in 33/33 TICS. p16 staining was positive in 12 of 14 TICs but patchy in 7/12.
Conclusions: The fallopian tubes of HGSCA exhibit two independent but related phenomena that may signify disruption of both genetic and epigenetic pathways. First, a globally distributed multifocal loss of PAX2 and ALDH1 expression is significantly associated with HGSCA and persists through the carcinogenic spectrum. Second, these two gene perturbations intersect in the fimbria with p53 mutations, where the transition to malignancy involves up-regulation of EZH2 and other biomarkers. Elevated EZH2 staining is a useful parameter for confirming STIC. Very small p53 signatures may not belong in the serous carcinogenic sequence.
Category: Gynecologic & Obstetrics
Tuesday, March 1, 2011 11:30 AM
Platform Session: Section D, Tuesday Morning