Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma

Our plain-English summary of Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma, by B.C. Christensen, J.J. Godleski, C.J. Marsit, et al (Carcinogenesis, 2008).

The study

• Authors: B.C. Christensen, J.J. Godleski, C.J. Marsit, E.A. Houseman, C.Y. Lopez-Fagundo, J.L. Longacker, R. Bueno, D.J. Sugarbaker, H.H. Nelson, K.T. Kelsey
• Journal: Carcinogenesis
• Published: 2008;29(8):1555-9
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rapidly fatal tumor with increasing incidence worldwide responsible for many thousands of deaths annually. Although there is a clear link between exposure to asbestos and mesothelioma, and asbestos is known to be both clastogenic and cytotoxic to mesothelial cells, the mechanisms of causation of MPM remain largely unknown. However, there is a rapidly emerging literature that describes inactivation of a diverse array of tumor suppressor genes (TSGs) via promoter DNA CpG methylation in MPM, although the etiology of these alterations remains unclear. We studied the relationships among promoter methylation silencing, asbestos exposure, patient demographics and tumor histology using a directed approach; examining six cell cycle control pathway TSGs in an incident case series of 70 MPMs. Promoter hypermethylation of APC, CCND2, CDKN2A, CDKN2B, HPPBP1 and RASSF1 were assessed. We observed significantly higher lung asbestos body burden if any of these cell cycle genes were methylated (P < 0.02), and there was a significant trend of increasing asbestos body counts as the number of methylated cell cycle pathway genes increased from 0 to 1 to >1 (P < 0.005). This trend of increasing asbestos body count and increasing number of methylated cell cycle pathway genes remained significant (P < 0.05) after controlling for age, gender and tumor histology. These data suggest a novel tumorigenic mechanism of action of asbestos and may contribute to the understanding of precisely how asbestos exposure influences the etiology and clinical course of malignant mesothelioma.

In plain English

This study looked at tumors from 70 patients with malignant pleural mesothelioma who had surgery at Brigham and Women's Hospital in Boston. The authors tested six cell cycle control genes (APC, CCND2, CDKN2A, CDKN2B, APPBP1 and RASSF1) for promoter methylation, a chemical change that can switch genes off. They compared this with asbestos body counts in each patient's normal lung tissue. Of 83 cases with count data, those with zero counts and three extreme outliers were left out. RASSF1 was methylated most often, in 33% of tumors, and tumors with RASSF1 methylation had higher asbestos body counts than those without. Higher asbestos body counts were associated with more methylated genes (P less than 0.005). This remained statistically significant (P less than 0.05) after accounting for age, gender and tumor histology, and older age was also a significant predictor. No single gene's methylation was significantly associated with self-reported asbestos exposure. The study did not identify fiber types in these patients. The authors concluded that epigenetic gene inactivation is a novel mechanism of asbestos action in this cancer.

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: Laboratory study of tumor tissue from an incident case series of patients with malignant pleural mesothelioma, relating gene methylation to lung asbestos body counts
• Who was studied: 70 patients with malignant pleural mesothelioma whose tumors were surgically removed at Brigham and Women's Hospital. There were 56 men and 14 women, aged 30 to 80 (mean 62), with 54 epithelioid, 14 mixed and 2 sarcomatoid tumors. Of 83 cases with asbestos body data, 10 with zero counts and 3 extreme outliers were excluded. Study years are not given.
• Exposure: Asbestos exposure was measured in two ways: as asbestos bodies per gram (wet weight) of normal lung tissue, and as self-reported exposure (53 of 70, 76%, reported exposure). Asbestos body counts ranged from 6 to 6211, mean 1000. Fiber types in these patients' lung tissue were not reported.
• Main results:
  • Methylation prevalence among the 70 tumors: RASSF1 33% (22 cases), APPBP1 20% (14), CDKN2A 13% (9), APC and CCND2 9% (6 each), CDKN2B 4% (3)
  • 40% of tumors (28) had no methylated cell cycle gene, 37% (26) had one and 23% (16) had more than one
  • Cases with RASSF1 methylation had higher asbestos body counts (mean 698) than cases without (mean 409) (P less than 0.01, Wilcoxon test)
  • No significant association was found between methylation at any one of the six genes and self-reported asbestos exposure
  • Asbestos body counts increased as the number of methylated cell cycle genes increased from 0 to 1 to more than 1 (P less than 0.005)
  • In an ordered logistic regression controlling for gender and tumor histology, age (P = 0.04) and asbestos body count (P less than 0.05) were significant predictors of a greater number of methylated cell cycle genes
  • Patients with methylation at any of the six genes were older (mean 64 years) than those without (mean 58 years) (P less than 0.01)
  • Men had higher asbestos body counts (mean 1218) than women (mean 213) (P less than 0.001, Wilcoxon test)
• The authors' conclusion: The authors concluded that their data show that epigenetic gene inactivation is a crucial and novel mechanism of asbestos action in the development of malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors noted that their findings do not necessarily mean that asbestos fibers interact directly with the DNA methylation machinery. They suggested that inflammation or faster tumor growth related to asbestos burden may instead select for these cells.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Pleural Mesothelioma, Mesothelioma, Mesothelial Cells, Causation, Tumor Suppressor Gene, Etiology, Histology.

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• Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer — D.H. Kim, H.H. Nelson, et al. (2001)
• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)
• Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients — A.A. Bahnassy, A.R. Zekri, et al. (2012)
• Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase — P.W. Szlosarek, P. Luong, et al. (2013)

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