Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients

Our plain-English summary of Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients, by A.A. Bahnassy, A.R. Zekri, A.A. Abou-Bakr, et al (Experimental and Molecular Pathology, 2012).

The study

• Authors: A.A. Bahnassy, A.R. Zekri, A.A. Abou-Bakr, M.M. El-Deftar, A. El-Bastawisy, M.A. Sakr, G.M. El-Sherif, R.M. Gaafar
• Journal: Experimental and Molecular Pathology
• Published: 2012;93(1):154-61
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive disease with a generally poor prognosis. Since escape from cell cycle checkpoint control is common in several solid tumors, the present study was performed to evaluate the role of some cell cycle regulatory genes in the development and progression of MPM.

Patients And Methods: Aberrant expression of p14(ARF), p16(INK4A), p21(waf), p27(KIP), p53, mdm2 and Rb was assessed in 55 MPM cases from Egypt using immunohistochemistry and PCR techniques. Results were correlated with clinico-pathological prognostic factors, overall and disease free survival (OS&DFS).

Results: Altered expression of p14(ARF), p16(INK4A), p21(waf), p27(KIP1), Rb, p53 and mdm2 proteins was detected in 50.9%, 54.5%, 53.3%, 61.8%, 53.3%, 58.2%, and 50.8% of cases, respectively. SV40 infection significantly correlated with p14(ARF), 16(INK4A), p27(kip1) and Rb aberrations (p=0.014, p=0.02, p=0.01, p=-0.01). Asbestos exposure significantly correlated with p53, p21(waf) and mdm2 aberrations (p=0.001, p=0.03, p=0.02). On multivariate analysis PS ≥ 2, p27(KIP1) and Rb aberrations were independent prognostic factors for OS (p=0.016, p=0.011, p=0.003) whereas on tumor recurrence, p27(KIP1) and Rb aberrations were independent prognostic factors for DFS (p=0.002, p=0.03, p=0.01).

Conclusions: MPM is a complex disease characterized by multiple genetic aberrations; some of them involve cell cycle regulatory genes. p14(ARF), p16(INK4A), Rb and p27(KIP1) seem to be involved in SV40-associated MPM whereas mdm2, p53 and p21(WAF) are related to asbestos exposure. In addition to recurrence and PS, only p27(KIP1)and Rb could be used as molecular prognostic markers in MPM.

Copyright © 2012 Elsevier Inc. All rights reserved.

In plain English

This prospective study at the National Cancer Institute, Cairo University, Egypt, examined tumors from 55 patients with malignant pleural mesothelioma seen from January 2005 to December 2007. Twenty normal lung samples served as controls. The researchers looked for abnormal levels of, or changes in the genes for, seven proteins that help control cell division: p14ARF, p16INK4A, p21waf, p27KIP1, p53, mdm2 and Rb. A history of asbestos exposure was recorded for 46 patients (83.6%). The article does not name the fiber types or describe the exposures. SV40 virus DNA was found in 29 patients (52.7%). Each protein was abnormal in between 50.8% and 61.8% of tumors. Asbestos exposure was significantly associated with changes in p53, mdm2 and p21WAF1. SV40 was associated with changes in p27KIP1, p16INK4A, Rb and p14ARF. In an analysis weighing several factors together, three things independently predicted shorter overall survival: a performance status (a fitness rating) of 2 or higher, loss of p27KIP1, and loss of Rb. The authors concluded that their data suggest two pathways to mesothelioma, depending on its possible cause, and that larger studies are needed to confirm this.

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: Prospective laboratory and clinical study of tumor tissue (immunohistochemistry and PCR), with results compared against clinical features and survival
• Who was studied: 55 patients with pathologically confirmed malignant pleural mesothelioma (29 males, 26 females; median age 46.4, range 20 to 70) who attended the National Cancer Institute clinics, Cairo University, Egypt, from January 2005 to December 2007; 20 normal lung tissue samples were used as controls
• Exposure: A positive history of asbestos exposure in 46 of 55 patients (83.6%). Fiber types, products, jobs and doses are not described. SV40 virus DNA was detected in 29 patients (52.7%).
• Main results:
  • In the 55 tumors, p53 was overexpressed in 58.2% and mdm2 in 50.8%, compared with normal tissue
  • Loss of p14ARF protein was seen in 28 tumors (50.9%) and loss of p16INK4A protein in 30 (54.5%)
  • p21Waf1 protein loss was seen in 29 cases (reported as 53.3%), p27Kip1 loss in 34 (61.8%), and reduced or lost Rb in 53.3%
  • Among the patients, asbestos exposure was significantly associated with p53, mdm2 and p21WAF1 changes (p=0.001, p=0.02, p=0.03)
  • The presence of SV40 DNA was significantly associated with abnormal p27KIP1 (p=0.01), p16INK4A (p=0.02), Rb (p=0.01) and p14ARF (p=0.014)
  • Advanced tumor stage was significantly associated with abnormal p16INK4A (p=0.001), p27KIP1 (p=0.001), p53 (p=0.043), mdm2 (p=0.01) and Rb (p=0.03)
  • In multivariate analysis, three factors were independent prognostic factors for reduced overall survival: performance status of 2 or higher, p27KIP1 aberrations and Rb aberrations (p=0.016, p=0.011, p=0.003)
  • Altered p27KIP1, altered Rb and tumor recurrence were independent prognostic factors for disease-free survival (p=0.03, p=0.001, p=0.02)
  • p21WAF changes showed no clinical significance and no impact on survival in this study
• The authors' conclusion: The authors concluded that their data suggest two different pathways for the development of malignant pleural mesothelioma that depend on the possible etiological agent(s). In their view:
• A p53, p14ARF and mdm2 pathway is a possible pathway in cases with prolonged asbestos exposure.
• A p16INK4A, p14ARF, p27kip1 and Rb pathway seems to be the key player in SV40-associated disease.
  They said larger studies are needed to confirm these results. They also concluded that p27KIP1 and Rb could be used to predict poor outcome.
• Limitations the authors state:
  • The authors state that studies on larger numbers of patients are needed to confirm the results
  • The authors state that a possible prognostic value of p16INK4A needs confirmation in a larger study

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Immunohistochemistry, SV40, Asbestos Exposure, Multivariate Analysis.

Related studies

• Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma — B.C. Christensen, J.J. Godleski, et al. (2008)
• Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation — B. Hasan, L. Greillier, et al. (2014)
• Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells — Y. Yoshikawa, A. Sato, et al. (2011)
• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• Aberrant expression of FoxP3 in a human T cell line possessing regulatory T cell‑like function and exposed continuously to asbestos fibers — M. Maeda, H. Matsuzaki, et al. (2018)
• Effect of simian virus large T antigen expression on cell cycle control and apoptosis in rat pleural mesothelial cells exposed to DNA damaging agents — V. Levresse, S. Moritz, et al. (1998)

Browse more research in Experimental and Molecular Pathology, or return to medical research.