Circulating autoantibodies as biomarkers of early stage, high grade serous ovarian cancer.

Abstract

INTRODUCTION: High grade serous epithelial ovarian cancers (HGSOCs) are typically diagnosed at an advanced stage, and account for ~90% of all ovarian cancer related deaths. Early diagnosis, prior to extra-ovarian spread, is associated with improved survival. There remains an unmet clinical need to identify novel biomarkers for the early-stage diagnosis of HGSOCs. Anti-tumor immune responses can generate auto-antibodies (AAbs) against tumor antigens well before the clinical manifestation of disease. We have performed a pilot study to identify AAbs as potential biomarkers for the detection of early-stage HGSOC. METHODS: Plasma samples were collected from chemo-naïve, previously untreated patients representing early (FIGO stage I) or advanced (FIGO stage III) HGSOC; and from patients with benign cystadenoma, benign cystadenofibroma or no diseases (n=20/group) and no prior history of malignancy. Samples were randomly assigned to either "discovery" or "validation" cohorts (n=10/group) and the presence and reactivity of AAbs (IgG, IgA, and IgM) determined using high-content protein arrays. Functional enrichment analyses were performed using Ingenuity Pathways Analysis and Gene Ontology. Enzyme-linked immunosorbent assays (ELISA) were developed against selected antigens, and their prevalence in each cohort assessed. RESULTS: In total 567 antigens were significantly associated with malignancy, and were functionally enriched for processes including cell cycle, growth and proliferation (early stage); and cell-cell signaling and inflammatory response (late-stage). Increased reactivity of two antigens - CCDC115 and HSF1 - was independently validated by ELISA in early stage patients, in both discovery and validation cohorts. Receiver-operator curve analysis at 90% sensitivity gave specificities of 88.9% (likelihood ratio 8.4, AUC 0.88) and 90% (likelihood ratio 4.5, AUC 0.96) respectively, for the detection of early-stage disease. CONCLUSIONS: Circulating auto-antibodies against CCDC115 and HSF1 represent potential biomarkers of early-stage HGSOC. This pilot study has established the workflow for expanded investigations to identify clinically relevant AAbs as markers of ovarian cancer.