DNA methylation profile of 28 potential marker loci in malignant mesothelioma

Abstract

SummaryPatients 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 noninvasively 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 environmentallyinduced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM vs. 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, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival. NIH Public Access

Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells

“…Interestingly, the DNA methylation status of MPM has been investigated by other authors that analyzed 28 genomic loci and found the presence of highly methylated genes [11]. To better link possible alterations of the DNA methylation levels with the already reported high genomic instability in mesothelioma cells, we focused our attention first on the methylation status of MPM cells verifying a robust decrease of DNA methylation involving megabases sized clusters of pericentromeric sequences (satellite 2).…”

“…Mesothelioma cells seem to recapitulate the epigenetic features of solid tumors since the presence of high genomic instability and a pattern of transcriptionally repressed tumor-suppressor genes, through DNA hypermethylation, has been demonstrated [7][8][9][10][11][12].…”

Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma

“…Cluster analysis was done using an agglomerative hierarchical clustering algorithm (23,25). For specimen clustering, pairwise similarity measures among specimens were calculated using Cluster 3.0 software 13 or Minitab 15 statistical software 14 based on the DNA methylation intensity measurements across all genes.…”

“…The relationship between promoter DNA hypermethylation and inflammation has been documented in many types of cancers, including MPM (10). It could be that asbestos exposure contributes to MPM formation through this relationship (11)(12)(13)(14), because it is known that asbestos induces continuous inflammation instead of directly transforming primary human mesothelial cells in tissue culture (15)(16)(17). In addition, recent cumulative studies of aberrant DNA methylation in human cancers showed high rates of aberrant promoter methylation in a subset of cancers, termed the CpG island methylator phenotype, which may also be contributing to MPM formation (18).…”

Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

“…RASSF1A, ESR1, IGFBP3, APC, CCND2, HPPBP1, BMP3b and BMP6 have been reported to be down-regulated by promoter methylation in mesothelioma. It has been suggested that these types of epigenetic changes contribute to tumorigenesis in mesothelioma (8)(9)(10)(11).…”