DNA methylation profile of 28 potential marker loci in malignant mesothelioma

Our plain-English summary of DNA methylation profile of 28 potential marker loci in malignant mesothelioma, by J.A. Tsou, J.S. Galler, A. Wali, et al (Lung Cancer, 2007).

The study

• Authors: J.A. Tsou, J.S. Galler, A. Wali, W. Ye, K.D. Siegmund, S. Groshen, P.W. Laird, S. Turla, M.N. Koss, H.I. Pass, I.A. Laird-Offringa
• Journal: Lung Cancer
• Published: 2007;58(2):220-30
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Patients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of non-invasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/DNA, we also examined the methylation of these markers in lung samples (age- or environmentally induced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM versus non-tumor lung samples was found for estrogen receptor 1 (ESR1; p = 0.0002), solute carrier family 6 member 20 (SLC6A20; p = 0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival.

In plain English

This laboratory study measured DNA methylation, a chemical change to DNA that can switch genes off, at 28 gene sites in tumor samples from 52 patients with malignant mesothelioma treated at the Karamanos Cancer Institute between May 2000 and February 2004. For comparison, the authors tested 38 cancer-free lung samples from lung cancer patients. Of the 49 patients with exposure information, 39 had been exposed to asbestos. Fiber types were not described. ESR1, SLC6A20 and SYK were more methylated in mesothelioma than in the comparison lung tissue, while APC, ATM and CDKN2B were more methylated in the lung tissue. Combining APC, SYK and SLC6A20 gave a sensitivity of 92% and a specificity of 73% in this tissue collection. MT1A methylation was higher in asbestos-exposed patients and MT2A higher in unexposed patients. Because many comparisons were made, the authors treated these findings cautiously, as suggestions for further study. They also noted that links between survival and LZTS1 and SLC6A20 would not stay statistically significant after correction for multiple comparisons. The authors concluded that the panel separated their samples with considerable sensitivity, but that specificity needs strengthening.

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 comparing DNA methylation at 28 gene sites in mesothelioma tumor tissue with non-tumor lung tissue, plus analysis of links with clinical features and survival
• Who was studied: Tumor samples from 52 patients with malignant mesothelioma treated at the Karamanos Cancer Institute, May 2000 to February 2004 (42 males, 9 females, gender unknown for one). The comparison group was 38 non-tumor lung samples from lung cancer patients at the Los Angeles County Hospital.
• Exposure: Asbestos exposure was recorded only as exposed (39 patients) or not exposed (10 patients), with data incomplete for three. No fiber types, products or jobs were given. The main measurement was DNA methylation at 28 gene sites.
• Main results:
  • ESR1, SLC6A20 and SYK were more frequently and/or more heavily methylated in mesothelioma than in non-tumor lung (p = 0.0002, 0.0022 and 0.0003, respectively).
  • APC, ATM and CDKN2B were more methylated in non-tumor lung than in mesothelioma (p less than or equal to 0.0001).
  • On its own, none of the three mesothelioma-elevated markers was strong (areas under the curve 0.70 to 0.73). The APC/SYK/SLC6A20 combination gave 92% sensitivity and 73% specificity in this tissue collection.
  • Among mesothelioma patients, median MT1A methylation (PMR) was 151 in asbestos-exposed patients versus 93 in unexposed patients (p = 0.050). Median MT2A methylation was 10 in exposed versus 21 in unexposed patients (p = 0.018).
  • Among mesothelioma patients, those exposed to asbestos were more likely to be male (p = 0.016) and to show lymph node involvement (p = 0.008).
  • Patients without SLC6A20 methylation had a relative hazard ratio of 2.14 (1.05 to 4.37) for death, with p = 0.022 unadjusted and 0.023 age-adjusted.
  • Patients with LZTS1 PMR of 130 or more had a relative hazard ratio of 1.93 (0.94 to 3.97), with p = 0.046 unadjusted and 0.065 age-adjusted.
• The authors' conclusion: The authors concluded that a three-marker methylation panel distinguished their mesothelioma and non-tumor lung tissues with considerable sensitivity, but that specificity needs to be strengthened by finding additional loci.
• Limitations the authors state:
  • Many associations were tested, so the authors interpreted the links between methylation and clinical features (gender, histology, asbestos exposure, lymph node involvement) cautiously, as suggestions for further study.
  • The sample size was relatively small, which made survival differences hard to observe.
  • The survival associations for LZTS1 and SLC6A20 would not remain statistically significant after correction for multiple comparisons.
  • Associations among the clinical variables (for example, asbestos-exposed patients being more often male) might drive several of the metallothionein associations at once.
  • Whether the markers work in bodily fluids such as effusions, plasma or serum was not tested.

Topics

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

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

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• Can CpG methylation serve as surrogate markers for immune infiltration in cancer? — M.D. Bacolod, F. Barany, et al. (2019)
• Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects — S. Guarrera, C. Viberti, et al. (2019)
• Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection — M. Suzuki, S. Toyooka, et al. (2005)
• Aberrant DNA methylation profile in pleural fluid for differential diagnosis of malignant pleural mesothelioma — M. Fujii, N. Fujimoto, et al. (2012)

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