Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome

Our plain-English summary of Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome, by B.C. Christensen, E.A. Houseman, J.J. Godleski, et al (Cancer Research, 2009).

The study

• Authors: B.C. Christensen, E.A. Houseman, J.J. Godleski, C.J. Marsit, J.L. Longacker, C.R. Roelofs, M.R. Karagas, M.R. Wrensch, R.F. Yeh, H.H. Nelson, J.L. Wiemels, S. Zheng, J.K. Wiencke, R. Bueno, D.J. Sugarbaker, K.T. Kelsey
• Journal: Cancer Research
• Published: 2009;69(1):227-34
• Cited by: 107 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mechanisms of action of nonmutagenic carcinogens such as asbestos remain poorly characterized. As pleural mesothelioma is known to have limited numbers of genetic mutations, we aimed to characterize the relationships among gene-locus-specific methylation alterations, disease status, asbestos burden, and survival in this rapidly fatal asbestos-associated tumor. Methylation of 1505 CpG loci associated with 803 cancer-related genes were studied in 158 pleural mesotheliomas and 18 normal pleura. After false-discovery rate correction, 969 CpG loci were independently associated with disease status (Q < 0.05). Classifying samples based on CpG methylation profile with a mixture model approach, methylation classes discriminated tumor from normal pleura (permutation P < 0.0001). In a random forests classification, the overall misclassification error rate was 3.4%, with <1% (n = 1) of tumors misclassified as normal (P < 0.0001). Among tumors, methylation class membership was significantly associated with lung tissue asbestos body burden (P < 0.03), and significantly predicted survival (likelihood ratio P < 0.01). Consistent with prior work, asbestos burden was associated with an increased risk of death (hazard ratio, 1.4; 95% confidence interval, 1.1-1.8). Our results have shown that methylation profiles powerfully differentiate diseased pleura from nontumor pleura and that asbestos burden and methylation profiles are independent predictors of mesothelioma patient survival. We have added to the growing body of evidence that cellular epigenetic dysregulation is a critical mode of action for asbestos in the induction of pleural mesothelioma. Importantly, these findings hold great promise for using epigenetic profiling in the diagnosis and prognosis of human cancers.

In plain English

This laboratory study measured DNA methylation, chemical tags that can switch genes off, at 1,505 sites in cancer-related genes. Samples came from 158 pleural mesothelioma patients at Brigham and Women's Hospital, Boston, and 18 nontumor pleura samples. Fiber types were not reported. Methylation differed between tumor and nontumor pleura at 969 sites; a classifier mislabeled 1 of 158 tumors and 5 of 18 nontumor samples. Among tumors, methylation classes were associated with asbestos body counts, accounting for gender (P < 0.03). Median survival was 12.5 months. Adjusted for age, gender and histology, classes 4 and 7 each had a death hazard ratio of 3.1 (95% CIs 1.4 to 7.0 and 1.3 to 7.4) versus class 2 (lowest median asbestos count). In 108 patients with lung counts, asbestos burden, recorded as a logged asbestos body count, had a death hazard ratio of 1.4 (95% CI 1.1 to 1.8), adjusted for these factors and methylation class; the increase it refers to is not stated. The authors concluded their data suggest epigenetic change is a major mode of action of asbestos in mesothelioma.

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 DNA methylation in surgically removed tumor and nontumor pleura tissue, with survival follow-up of the patients. Patients came from a 2002 pilot study and an incident case series that began in 2005.
• Who was studied: 158 patients with pleural mesothelioma whose tumors were surgically removed at Brigham and Women's Hospital, Boston (120 men, 38 women, ages 30 to 80). There were also 18 nontumor parietal pleura samples taken from uninvolved sites during surgery. Patients came from a 2002 pilot study (n = 70) and a case series that began in 2005 (n = 88).
• Exposure: Asbestos was assessed in two ways. Patients reported their exposure history by questionnaire or interview: 112 (74%) of mesothelioma patients reported exposure, as did 13 (72%) of pleura donors. Asbestos bodies were also counted in lung tissue. Counts were available for 108 (68%) of mesothelioma patients and were summarized as a logged asbestos body count (range 0 to 5.5, mean 2.16). The article does not specify fiber types.
• Main results:
  • After correction for multiple testing, methylation differed between tumor and nontumor pleura at 969 CpG sites. Of these, 727 had more methylation in nontumor pleura and 242 had more methylation in tumors.
  • In a random forest classification of all samples, 1 tumor (less than 1%) was misclassified as nontumor, and 5 of 18 nontumor samples (28%) were misclassified as tumors. The overall misclassification error rate was 3.4%.
  • The 158 tumors formed seven methylation classes. Class membership predicted lung asbestos body count (permutation P < 0.04), and this remained significant after controlling for gender (P < 0.03).
  • In tumors, methylation at the CDKN2A, CDKN2B and RASSF1 genes was positively associated with asbestos body counts. Methylation at two sites in MT1A was also positively associated with asbestos burden.
  • Median survival of the patients was 12.5 months, with 67 months of follow-up.
  • In the model of all 158 cases, controlled for age, gender and histology, women had about half the risk of death of men (HR 0.5; 95% CI 0.3 to 0.96). Patients with mixed histology tumors had greater risk than those with epithelial tumors (HR 2.7; 95% CI 1.7 to 4.4). In the 108 cases with asbestos data, the female hazard ratio was 1.5 (95% CI 0.6 to 3.5; P = 0.38).
  • In the model of all 158 cases, adjusted for age, gender and histology but not asbestos burden, methylation class 4 had a hazard ratio of death of 3.1 (95% CI 1.4 to 7.0) compared with class 2. Class 7 also had a hazard ratio of 3.1 (95% CI 1.3 to 7.4). Class 2 was the class with the lowest median asbestos count.
  • The model of the 108 cases with asbestos body data was adjusted for age, gender, histology and methylation class. In it, asbestos burden, recorded as a logged asbestos body count, had a hazard ratio of death of 1.4 (95% CI 1.1 to 1.8). The article does not state the size of increase in log burden the hazard ratio refers to. In the same model, methylation class 4 had a hazard ratio of 2.8 (95% CI 1.1 to 7.1).
• The authors' conclusion: The authors concluded that epigenetic alterations are extremely common in mesothelioma and distinguish it from normal pleura. They found these alterations associated with asbestos burden and predictive of clinical outcome. They stated that their data suggest epigenetic modification is a major mode of action of asbestos in mesothelioma.
• Limitations the authors state:
  • The authors stated that they could not directly distinguish between alternative explanations for why so many genes were methylated.
  • The authors stated that they cannot exclude that methylation at specific gene sites, rather than overall patterns, is what predicts survival.
  • The array examined only about two CpG sites per gene; the authors noted that sequencing methods would give more detail.
  • Two methylation classes contained a mix of tumor and nontumor samples.

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, Pleura, Discovery, Asbestos Body Formation, Hazard Ratio, confidence interval, Mesothelioma, Prognosis.

Related studies

• Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma — B.C. Christensen, E.A. Houseman, et al. (2010)
• Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma — B.C. Christensen, J.J. Godleski, et al. (2008)
• The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma — H.H. Nelson, L.M. Almquist, et al. (2011)
• Malignant peritoneal mesotheliomas of rats induced by multiwalled carbon nanotubes and amosite asbestos: transcriptome and epigenetic profiles — S.M. Reamon-Buettner, S. Rittinghausen, et al. (2024)
• Solitary fibrous tumors of the pleura: clinical characteristics, surgical treatment and outcome — P. Magdeleinat, M. Alifano, et al. (2002)
• CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome — E. Ortolan, A. Giacomino, et al. (2014)

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