DUSP4 overexpression is associated with MAPK pathway alterations in low-grade serous ovarian cancer

Abstract

MAPK pathway alterations, most commonly KRAS , NRAS , and BRAF mutations, occur in approximately 50–60% of ovarian low-grade serous carcinomas (LGSCs). We sought to identify clinically translatable markers of MAPK pathway activation in LGSC samples. Differential gene expression analysis revealed overexpression of regulators and effectors of MAPK signaling in RAS/RAF -mutated ( n = 33) versus wildtype ( n = 31) LGSCs, with DUSP4 showing the strongest association. A previously defined MAPK pathway activation signature (MPAS) distinguished RAS/RAF- mutated from RAS/RAF -wildtype tumors, while identifying occasional RAS/RAF -wildtype tumors with alternative MAPK-activating gene alterations. Immunohistochemical analysis of DUSP4, cyclin D1, and p-ERK in 192 borderline/malignant low-grade serous tumors revealed DUSP4 as the most accurate predictor of RAS/RAF mutation status (sensitivity: 82.1%, specificity: 90.9%). In an exploratory analysis of 22 ovarian cancer patients treated with MEK inhibitor therapy, DUSP4 and cyclin D1 H-scores were significantly associated with tumor shrinkage (both p < 0.01), although neither marker significantly differed between RECIST-defined responders and non-responders. DUSP4 expression is common in borderline/malignant low-grade serous tumors with MAPK pathway gene alterations and may help triage cases for molecular testing to inform therapeutic stratification.