Oncogenic BRAF and KRAS mutations in endosalpingiosis

Endosalpingiosis, a microscopic lesion composed of ectopic Fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian serous borderline tumour or low-grade serous carcinoma, but its pathogenic significance remains unclear. Using laser-capture microdissection and droplet digital PCR, we investigated whether endosalpingiosis harbours the driver mutations in BRAF and KRAS that characterise ovarian low-grade serous neoplasms. Somatic mutations were detected in 14 (33%) of 43 endosalpingiotic lesions analysed. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumour, mutations were identified in endosalpingiotic lesions from 11 (52%) women, with most cases (10/11, 91%) demonstrating identical mutations in both tumour and endosalpingiosis. In contrast, of 13 cases of endosalpingiosis not associated with an ovarian tumour, only one harboured a KRAS mutation. The proliferative activity as assessed by Ki-67 immunohistochemistry was lower in endosalpingiosis than in low-grade serous tumours, and endosalpingiosis with either a BRAF or KRAS mutation had a significantly lower Ki-67 index than those without. Ectopic expression of KRAS^G12V in Fallopian tube epithelial cells led to ERK phosphorylation, p21 induction, growth arrest and cellular senescence. In conclusion, we demonstrate that endosalpingiosis represents an interesting example of cancer driver mutations in deceptively normal-appearing cells, which may be prone to neoplastic transformation upon bypass of endogenous oncosuppressive mechanisms.