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

Our plain-English summary of Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma, by A. De Rienzo, M.H. Coleman, B.Y. Yeap, et al (Cancers, 2021).

The study

• Authors: A. De Rienzo, M.H. Coleman, B.Y. Yeap, D.T. Severson, B. Wadowski, C.E. Gustafson, R.V. Jensen, L.R. Chirieac, W.G. Richards, R. Bueno
• Journal: Cancers
• Published: 2021;13(3)
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This retrospective study used malignant pleural mesothelioma tumors removed at one Boston hospital, 1992 to 2009. The authors asked whether estrogen-related gene expression in tumors helps explain women's longer survival after surgery. Among estrogen-receptor-binding genes, RERG varied most in one initial set of 44 tumors and ranked third in another of 39. In both sets, higher RERG expression was associated with longer survival. A third group of 129 patients (66 women, 63 men) with epithelioid tumors removed by extrapleural pneumonectomy had men and women matched on age and lymph node status. There, women lived longer than men (median 18.2 versus 14.0 months). Women with high RERG had a median survival of 33.1 months, versus 15.9 months for women with low RERG. Men did worse than high-RERG women regardless of RERG level. Estrogen receptors could not be detected in the tumors. Blood estradiol (42 patients) was not associated with survival. The authors concluded that RERG may play a role in women's survival advantage and that more study is needed. Asbestos exposure was self-reported; no analysis of its link to RERG or survival was reported.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-institution retrospective cohort analysis of tumor gene expression (microarray) and survival after surgery
• Who was studied: Patients who had surgery for malignant pleural mesothelioma at Brigham and Women's Hospital, Boston, with tumor specimens collected 1992 to 2009. There were two discovery datasets: Sentrix, 39 patients (5 women, 34 men), and Codelink, 44 patients (16 women, 28 men). The validation cohort was selected as 132 patients; 129 were analyzed (66 women, 63 men). All had epithelioid tumors removed by extrapleural pneumonectomy, and men and women were matched on age and lymph node status.
• Exposure: The factor studied was tumor expression of the RERG gene and other estrogen-related genes. High versus low RERG expression was split at the median. The authors also looked at estrogen receptor protein and gene expression and at blood estradiol levels. Asbestos exposure was self-reported and listed in the patient table (validation cohort: 76 yes, 43 no, 10 unknown). No analysis of its relationship with RERG or survival was reported.
• Main results:
  • Among genes in the Estrogen Receptor Binding annotation, RERG showed the highest variance in the Codelink data (44 patients) and was third-ranked in the Sentrix data (39 patients).
  • In the discovery datasets, patients with high RERG expression lived longer than those with low expression. Sentrix: median overall survival 12.8 versus 6.5 months (HR = 2.37, p = 0.014). Codelink: 40.7 versus 6.9 months (HR = 4.8, p < 0.001).
  • In the sex-matched validation cohort of 129 patients, women lived longer than men: median survival 18.2 months for women and 14.0 months for men (HR = 1.64, p = 0.015).
  • In the validation cohort, men and women had similar distributions of RERG expression (p = 0.66).
  • Women with high RERG had a median survival of 33.1 months; this group was the reference. Compared with them, the other groups did worse: women with low RERG, 15.9 months (HR = 2.05, p = 0.019); men with low RERG, 10.5 months (HR = 3.04, p < 0.001); men with high RERG, 14.1 months (HR = 2.04, p = 0.022).
  • Among men, no significant association between RERG expression and survival was observed.
  • In 95 tumors tested, staining for estrogen receptor alpha protein was negative in all samples. Attempts to show estrogen receptor beta protein were unsuccessful. Gene expression of both estrogen receptors (ESR1, ESR2) was below the threshold for reliable expression.
  • Blood estradiol levels in 42 patients (25 male, 17 female) were not associated with overall survival (HR = 0.84, p = 0.634).
• The authors' conclusion: The authors concluded that RERG expression was an independent predictor of prognosis in women, suggesting it may play a role in women's survival advantage. Because estrogen receptors were not detected and estradiol was not related to survival, they said more analysis is needed to determine RERG's role and any link with estrogen.
• Limitations the authors state:
  • RERG was measured only as gene (transcript) expression. Available antibodies did not work to show RERG protein in the tumors, and protein levels do not always match transcript levels.
  • The validation cohort required selecting men to match the available women, who are generally younger and have epithelioid disease. This introduces selection and age biases compared with unselected cohorts.
  • Additional treatments such as chemotherapy and radiation may bias the survival analysis. However, the authors observed no differences in such treatment between men and women in the validation cohort.
  • The study could not demonstrate estrogen receptor gene or protein expression in the tumors.
  • The lack of a link between blood estradiol and survival may reflect the small number of patients with plasma samples.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Asbestos Exposure, Discovery.

Related studies

• Validation of a Gene Expression Test for Mesothelioma Prognosis in Formalin-Fixed Paraffin-Embedded Tissues — A. De Rienzo, R.W. Cook, et al. (2017)
• Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice — S. Funahashi, Y. Okazaki, et al. (2020)
• WT1 expression in the female genital tract — C. Bárcena, E. Oliva (2011)
• Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection — D.J. Sugarbaker, R.R. Gill, et al. (2013)
• Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume — R.R. Gill, W.G. Richards, et al. (2012)
• Attributable risk: advantages of a broad definition of exposure — S. Wacholder, J. Benichou, et al. (1994)

Browse more research in Cancers, or return to medical research.