Mutational Analysis of BRAF and KRAS in Atypical Proliferative (Borderline) Serous Tumors of the Ovary and Associated Peritoneal Implants from a Population-Based Cohort in Denmark
Laura Ardighieri, Robert J Kurman, Russel Vang, Ie-Ming Shih. Johns Hopkins University School of Medicine, Baltimore, MD
Background: Atypical Proliferative (Borderline) Serous Tumors (APSTs) are a unique group of ovarian tumors characterized by the presence of “peritoneal implants”. Peritoneal implants are subdivided in two morphological subtypes, non-invasive (NIIP) and invasive implants (IIP), the latter being considered as the most important prognostic marker. Whole genome exome sequencing analysis has revealed KRAS and BRAF as the main mutated genes in ovarian APSTs; however, the molecular nature of peritoneal implants remains largely unknown because of conflicting results in previous studies that focused on a small number of cases.
Design: The aim of this study is to compare KRAS/BRAF mutational status between APSTs and their associated peritoneal implants. 39 patients with advanced stage APSTs were identified from a nation-wide tumor registry in Denmark. For each patient the primary ovarian APST and one or more implants were selected to perform laser-microdissection and KRAS/BRAF mutational analysis, for a total of 92 tumoral lesions (39 APSTs, 43 NIIPs and 10 IIPs).
Results: KRAS and BRAF mutations were identified in 27 (69.3%) and 3 (7.7%) of 39 APSTs, respectively, while the remaining 9 APSTs (23%) were wild-type for both genes. KRAS and BRAF mutations were identified in 34 (64.1%) and 5 (9.4%) of 53 peritoneal implants, for total of 39/53 KRAS or BRAF mutated implants (73,6%), while the remaining 14 implants (26.4%) were wild-type for both genes. Comparison of the mutational status between the primary APST and the related peritoneal implant for each patient (“APST-implant pair”) showed the same mutations in 34/37 APST-implant pairs associated with KRAS mutated primary APSTs and in 5/5 APST-implant pairs associated with BRAF mutated primary APSTs; no mutations were identified in 11/11 APST-implant pairs associated with KRAS and BRAF wild type primary APSTs. Overall the same mutational status of KRAS/BRAF was concordant in 50/53 APST-implant pairs (94,3%), independently of the type of implants (concordance was found in 40/43 APST-NIIP pairs (93%) and in 10/10 APST-IIP pairs (100%)).
Conclusions: We provide evidence that most peritoneal implants, regardless of their types, i.e., NIIPs vs. IIPs, harbor either KRAS or BRAF mutations. The demonstration of an identical mutational status of KRAS and BRAF between primary ovarian APSTs and related implants strongly supports the hypothesis that most non-invasive and invasive implants share a common origin with the associated ovarian tumor.
Category: Gynecologic & Obstetrics
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 163, Wednesday Morning