Abstract B21: Oncogenic BRAF and KRAS mutations in endosalpingiosis

Abstract

Abstract Endosalpingiosis, or ectopic fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian low-grade serous borderline tumor or carcinoma, but the pathogenic significance of these microscopic lesions remains unclear. Using laser-capture microdissection and digital droplet PCR, we investigated whether endosalpingiosis harbors the driver mutations in BRAF and KRAS, commonly seen in low-grade serous tumors. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumor, mutations were identified in 11 (52%) cases and the identical mutation was shared between the tumor and endosalpingiosis in 10/11 cases. In contrast, of 12 cases of endosalpingiosis not associated with an ovarian tumor, only 1 harbored a KRAS mutation. Across mutation-positive cases, the median mutant allelic frequency was 37% (range: 12 – 67%). Ki-67 immunohistochemical staining revealed significantly decreased proliferative index in endosalpingiosis relative to low-grade serous tumors, but no difference with eutopic tubal epithelium. BRAF or KRAS-mutated endosalpingiosis had significantly lower Ki-67 index compared to lesions lacking mutations in both genes. Functional studies using fallopian tube epithelial cell cultures demonstrate that enforced expression of KRAS-G12V causes phosphorylation of downstream ERK, with associated growth impairment and induction of p21, suggesting oncogene-induced senescence. We demonstrate that endosalpingiosis represents a striking example of cancer driver mutations in deceptively normal-appearing cells, signifying this innocuous-appearing lesion as a monoclonal proliferation with neoplastic potential. Citation Format: M. Herman Chui, Ie-Ming Shih. Oncogenic BRAF and KRAS mutations in endosalpingiosis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B21.