Abstract
Simple SummarySex differences in tumor incidence and mortality have been documented for many different cancer types. In malignant pleural mesothelioma, a deadly disease, many studies have shown that women not only develop this cancer less frequently than men, but those who do are likely to live longer after surgery. These differences have been postulated to reflect circulating estrogen levels and tumor expression of estrogen receptors that may influence tumor progression. We identified high expression of the RAS like estrogen regulated growth inhibitor gene (RERG), to correlate with longer survival after surgery among women. Survival in men was not associated with RERG expression. Additionally, we found no association between survival and tumor expression of estrogen receptor genes. Additional studies are needed to elucidate any role RERG may play in mesothelioma, and whether estrogen may be involved.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.
Highlights
Many cancers exhibit significant differences between men and women in terms of incidence, prognosis and mortality [1]
To identify genes associated with estrogen signaling potentially associated with longer survival in women with Malignant pleural mesothelioma (MPM), genes in the Estrogen Receptor Binding annotation of the Gene Ontology database (GO:ERB) were investigated using MPM datasets based on two microarray platforms (Codelink and Sentrix [17])
RAS like estrogen regulated growth inhibitor (RERG) was found to be highly expressed across tumors in both cohorts
Summary
Many cancers exhibit significant differences between men and women in terms of incidence, prognosis and mortality [1]. MPM exhibits a strong sex bias in terms of distribution (M:F = 4:1), likely due to occupational exposure and women with MPM have consistently demonstrated a significant survival advantage [2,3,4], even when controlling for other known prognostic factors including age, stage, and histologic subtype (ranging from epithelioid to sarcomatoid differentiation with increasingly poor prognosis) [5,6]. This survival advantage has been attributed to higher probability of occupational exposure to asbestos in men, whereas women generally have a non-occupational or secondhand exposure through spouses’ clothing, low-level environmental exposure, and other sources [5,6]. There is growing evidence suggesting that the female survival advantage in cancer may be the result of more complex interactions between sex hormones, genetic variability, including sex chromosomes and environment [8]
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