Abstract
Simple SummaryFamilial studies connect variants in the X-linked gene MAGEC3 to early-onset ovarian cancers. In this retrospective cohort study, we determined that, unlike other MAGE family members, the MAGEC3 protein is normally expressed in ovarian tissue but is lost in half of the ovarian cancers. Similar to other predisposition genes like BRCA2, survival modeling suggests that expression loss is associated with favorable progression-free survival, and continued expression is associated with response to platinum therapy. Because of the assumed antigenicity of MAGE genes, we tested and observed associations with lymphocyte infiltration, NY-ESO-1 seropositivity, and the co-expression of tumor antigens at Xq28. Using transcriptomic modeling, we predicted that MAGEC3 expression is associated with stress-related cell cycle stalling and DNA repair pathway expression.Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. 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 immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate 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 expressed 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) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.
Highlights
We previously reported the linkage between early-onset, BRCA negative ovarian cancers and a locus on Xq27.2 that contains the gene MAGEC3 [1] identified from inheritance patterns in the Familial Ovarian Cancer Registry (Buffalo, NY, USA) [2] that heavily favored clustering among sisters likely due to a father who transmits the risk allele [3]
Given that ovarian cancers are highly immunogenic, we considered the association between MAGEC3 and the count of CD8+ tumor-infiltrating lymphocytes (TILs)
We reported that MAGEC3 was difficult to measure by bulk RNA sequencing and subsequently developed an RNA-based linear model to predict MAGEC3 protein levels learned from labeled data
Summary
We previously reported the linkage between early-onset, BRCA negative ovarian cancers and a locus on Xq27.2 that contains the gene MAGEC3 [1] identified from inheritance patterns in the Familial Ovarian Cancer Registry (Buffalo, NY, USA) [2] that heavily favored clustering among sisters likely due to a father who transmits the risk allele [3]. The MAGE family has been studied as bona fide tumor-specific antigens, and we have previously reported on their individual and combined effects on ovarian cancer prognosis [9,10]. MAGE genes are associated with poor prognosis, one-third of MAGE family members are “Type II” MAGE genes that are constitutively expressed and perform essential tasks in many tissues. The level of tissue-specific expression and clinical implications of MAGEC3 expression are currently unknown. We measured MAGEC3 protein levels in ovarian cancers and normal tissues. We measured MAGEC3 levels in samples of various tissue types containing matched RNA sequencing data which were used to build a robust predictor of protein expression. Clinical correlations and molecular associations related to MAGEC3 expression (or loss of expression) elucidate MAGE biology
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