Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

Abstract

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

Keywords: RERG; estrogen; malignant pleural mesothelioma; sex; survival.

Figure 1

Survival analysis of the patients with malignant pleural mesothelioma (MPM) included in the Sentrix and Code-Link datasets according to RERG expression levels. Kaplan-Meier curves of overall survival according to RERG expression in the Sentrix (n = 39) (A) and CodeLink (n = 44) (B) datasets. Red and blue curves represent RERG expression lower and higher than the median levels, respectively. Overall survival was calculated from date of surgery. Survival curves were truncated at 36 months.

Figure 2

Survival analysis of the patients with MPM included in the selected cohort according to sex. Kaplan-Meier curves of overall survival between the two sexes in the selected datasets (n = 129). Red and blue curves represent male and female, respectively. Overall survival was calculated from date of surgery. Survival curves were truncated at 36 months.

Figure 3

RERG analyses in relation to sex (A) and survival (B) in the Affymetrix cohort. Box plots (outliers not shown) illustrating RERG expression for female (n = 66) and male (n = 63) MPM patients (A). Kaplan-Meier curves of overall survival according to sex and RERG expression (n = 129) (B). Green and blue indicate low and high RERG expression in women, respectively, whereas black and red indicate low and high RERG expression in men. Overall survival was calculated from date of surgery. Survival curves were truncated at 36 months.

Figure 4

Differential expression analysis of 129 MPM tumors. Volcano plots representing differentially expressed genes between (A) tumors expressing high RERG vs. tumors exhibiting low RERG in women; (B) women and men; (C) tumors of women expressing high RERG vs. all the other samples. The −log10 false discovery rate (FDR) was plotted against log2 fold change (FC) values for all tested genes. The symbols on the negative and positive values of x-axis in each figure represent downregulated and upregulated genes, respectively. Symbols corresponding to significantly differentially expressed genes (FDR < 0.05) and top hit genes (FDR < 0.05 and 2-fold change) are colored in yellow and red, respectively.