Expression Profiling of a Candidate Precursor to Pelvic Serous Cancer in the Distal Fallopian Tube (p53 Signature)
KK Mehra, SW Tay, M Mehrad, CP Crum, W Xian. Brigham and Women's Hospital, Boston, MA; Institute of Molecular Biology, Singapore, Singapore
Background: A link between many pelvic serous cancers and the distal fallopian tube has been strengthened by the discovery of a putative precursor that shares many features with serous carcinoma and resides in the distal fallopian tube – the p53 signature. This entity is phenotypically (secretory cell), immunophenotypically (p53 staining), genotypically (p53 mutations) and in some cases topographically linked to early (intraepithelial) carcinomas in the fimbria. The extremely small size of the p53 signatures has hampered efforts to assess its expression profile.
Design: Consecutively banked (frozen) fimbria from controls (benign conditions) and subjects with ovarian cancer were sectioned, immunostained for p53 and examined for the presence of p53 signatures. If p53 signatures were detected, serial sections from the tissue block were placed on membrane slides, the presence of the precursor confirmed by immunostaining of subsequent sections and RNA isolated by laser capture microdissection. Extracted RNA was amplified and hybridized to Affymetrix Human Exon 1.0 ST Array and the resulting data was resolved by Partek Genomics Suite software and Ingenuity Pathway Analysis software.
Results: Two p53 signatures were identified from analysis of 25 frozen tissue blocks. Hybridization efficiency of the amplified p53 signature RNA exceeded 80%. A supervised comparison of one p53 signature revealed deregulation of the p53 pathway compared to the normal epithelium. p53 was down-regulated by almost 2-fold in the p53 signature and was accompanied by down-regulation of MDM2; consistent with reduced proteasomal degradation of p53 and its accumulation in the secretory cell nuclei. PI3K and AKT, upstream of p53, were also down-regulated in the p53 signature, consistent with their role in the phosphorylation of MDM2 and potential loss of proteasomal degradation of p53. Disturbed expression in other genes participating in apoptosis, cell-cycle control and angiogenesis was observed.
Conclusions: This is the first report describing the gene expression profile of the p53 signature and the abnormalities of the p53 and related pathways that could contribute to the early phases of serous carcinogenesis. The relationship of these pathways to both the pathogenesis of the p53 signature and subsequent steps in serous carcinogenesis will be discussed.
Category: Gynecologic & Obstetrics
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 147, Tuesday Afternoon