Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma

Our plain-English summary of Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma, by B.C. Christensen, E.A. Houseman, G.M. Poage, et al (Cancer Research, 2010).

The study

• Authors: B.C. Christensen, E.A. Houseman, G.M. Poage, J.J. Godleski, R. Bueno, D.J. Sugarbaker, J.K. Wiencke, H.H. Nelson, C.J. Marsit, K.T. Kelsey
• Journal: Cancer Research
• Published: 2010;70(14):5686-94
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Development of mesothelioma is linked mainly to asbestos exposure, but the combined contributions of genetic and epigenetic alterations are unclear. We investigated the potential relationships between gene copy number (CN) alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n = 23). There were no instances of significantly correlated CN alteration and methylation at probed loci, whereas averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations. In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes. Further, there was evidence that this association was partially attributable to prevalent allele loss at the DNA methyltransferase gene DNMT1. Our findings define a strong association between global genetic and global epigenetic dysregulation in mesothelioma, rather than a discrete, local coordination of gene inactivation.

(c)2010 AACR.

In plain English

This laboratory study examined tumors from 23 patients with pleural mesothelioma who had surgery at Brigham and Women's Hospital. They were part of a larger series of 158 mesotheliomas. The authors compared gains or losses of gene copies (copy number changes) with DNA methylation, a chemical mark that can switch genes off. Frequent losses included 3p21.3 and 22q (44% of tumors each) and 9p21 (39%). The extent of copy number change was not significantly associated with age, gender, tumor histology or asbestos exposure burden. No single DNA site showed a significant link between the two kinds of change, and only two of 663 genes did. However, the overall extent of copy number change differed significantly between tumor groups defined by methylation pattern. Seven tumors (30%) had lost a copy of DNMT1, a gene that maintains methylation. After adjusting for age, gender and histology, this loss was associated with shorter survival (hazard ratio 5.07; 95% confidence interval 1.23 to 20.9). The authors concluded that overall genetic and overall epigenetic disruption were strongly associated 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 molecular study of a tumor case series. Gene copy number (from SNP arrays) was compared with DNA methylation profiles.
• Who was studied: 23 pleural mesotheliomas, each with matched blood DNA, taken from the incident case series that began in 2005. They were drawn from 158 mesotheliomas, plus 18 nontumor parietal pleura samples, obtained at surgery at Brigham and Women's Hospital through the International Mesothelioma Program.
• Exposure: The study measured genetic (copy number) and epigenetic (methylation) changes within tumors. It did not study a specific fiber type or product. Patients' asbestos exposure burden was tested only against the extent of copy number change.
• Main results:
  • Among the 23 tumors, prevalent allele losses included 1p21.3 (30%), 4q22 (30%), 4q31-32 (35%), 3p21.3 (44%), 6q25 (39%), 9p21 (39%) and 22q (44%).
  • The extent of copy number alteration was not significantly associated with age, gender, histology or asbestos exposure burden.
  • No individual DNA locus showed a significant correlation between copy number and methylation (Q less than 0.05).
  • At the gene level, only ITGB1 and FYN, out of 663 genes, had significantly correlated copy number and methylation. These correlations were not due to combined allele loss and hypermethylation.
  • The extent of copy number alteration differed significantly among methylation profile classes (permutation test P less than 0.02). Classes 2, 6 and 7 showed more alteration than classes 1, 3 or 4.
  • DNMT1 had copy number loss in seven tumors (30%). Tumors without DNMT1 allele loss showed a significant trend toward higher methylation than tumors with loss (P = 0.05).
  • In a Cox model controlling for age, gender and tumor histology, DNMT1 allele loss was associated with significantly reduced patient survival (HR 5.07; 95% CI 1.23 to 20.9).
• The authors' conclusion: The authors concluded that their findings define a strong association between global genetic and global epigenetic dysregulation in mesothelioma, rather than a discrete, local coordination of gene inactivation.
• Limitations the authors state:
  • The global association could be influenced by bias in methylation measurement at regions with copy number change. The authors cite their earlier work showing the platform is not subject to significant bias of this kind.
  • In human tumors it may not be possible to estimate the timing of critical events.
  • Other gene inactivation mechanisms, such as miRNA/mRNA alterations and gene mutation, were not measured.

Topics

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

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

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