Primary Ovarian Mucinous Tumors (OMT) Lack Loss of MLH-1 and MGMT and Are Characterized by KRAS Mutations and Aberrant p53 Expression When They Progress to Carcinoma
M Gupta, JL Gonzalez, JA Lefferts, A Quer, GJ Tsongalis, E Oliva. Dartmouth Hitchcock Medical Center, Lebanon, NH; Massachusetts General Hospital, Boston, MA
Background: Primary OMTs show a morphologic spectrum from benign (BMT) to borderline (BOT) to carcinoma (MCA). Most of these tumors, especially in the BOT and MCA categories, show close morphological and some immunohistochemical overlap with tumors of the gastrointestinal tract. The goals of this study were to analyze the molecular events at each step of progression in primary OMTs and to determine whether microsatellite instability and aberrant methylation play a role in these tumors, similar to what has been reported in their gastrointestinal counterparts.
Design: Forty-four primary OMTs including 16 BMT, 18 BOT and 10 MCA (all gastrointestinal type) were retrieved and slides were reviewed. Immunohistochemistry for p53 (tumor suppressor gene), beta-catenin (Wnt signaling pathway), MLH-1 (microsatellite instability), and MGMT (O6 methylguanine methyltransferase; surrogate marker of gene promoter methylation),and mutational analysis for KRAS (by DNA sequencing of exon 1; codons 12,13) and BRAF (V600E mutation by PCR using allele specific primers) were performed in all cases. Confluent, strong p53 immunoexpression in discrete foci with > 50% of nuclei stained was considered positive. Immunostaining for beta-catenin was classified as membranous, cytoplasmic or nuclear and complete loss of nuclear staining for MLH-1 or MGMT was recorded.
Results: One/16 BMT, 3/18 BOT and 3/10 MCA showed aberrant p53 expression. Staining for beta-catenin was always membranous with no nuclear or cytoplasmic positivity. Intact nuclear staining for MLH -1 and MGMT was present in all cases. KRAS mutations (analysis successfully performed in 39/44 cases) were found in 0/16 BMT, 10/17 BOTs and 6/6 MCAs. No BRAF mutations were identified. Four tumors (2 BOT and 2 MCA) with KRAS mutations also showed aberrant p53 expression.
Conclusions: Our results indicate that despite morphological similarities with gastrointestinal tumors, primary OMT are genetically distinct in several aspects: 1) microsatellite instability, methylation abnormalities and aberrations of Wnt signaling pathway, and BRAF mutations are not prevalent, and 2) KRAS mutations are a frequent event occurring typically in BOTs and MCAs. Interestingly, this genetic profile (KRAS mutations and/or sporadic p53 overexpression) overlaps with that reported in the sequence of low-grade serous tumors of the ovary.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 150, Monday Morning