Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Abstract

Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian can-cers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immuno-histochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multi-variate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially ex-pressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA’s OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson’s r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hall-mark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.