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. 2009 Aug 1;69(15):6315-21.
doi: 10.1158/0008-5472.CAN-09-1073. Epub 2009 Jul 28.

Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles

Brock C Christensen  1 , Carmen J Marsit, E Andres Houseman, John J Godleski, Jennifer L Longacker, Shichun Zheng, Ru-Fang Yeh, Margaret R Wrensch, Joseph L Wiemels, Margaret R Karagas, Raphael Bueno, David J Sugarbaker, Heather H Nelson, John K Wiencke, Karl T Kelsey
Affiliations

Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles

Brock C Christensen et al. Cancer Res. .

Abstract

Pathologic differentiation of tissue of origin in tumors found in the lung can be challenging, with differentiation of mesothelioma and lung adenocarcinoma emblematic of this problem. Indeed, proper classification is essential for determination of treatment regimen for these diseases, making accurate and early diagnosis critical. Here, we investigate the potential of epigenetic profiles of lung adenocarcinoma, mesothelioma, and nonmalignant pulmonary tissues (n = 285) as differentiation markers in an analysis of DNA methylation at 1413 autosomal CpG loci associated with 773 cancer-related genes. Using an unsupervised recursively partitioned mixture modeling technique for all samples, the derived methylation profile classes were significantly associated with sample type (P < 0.0001). In a similar analysis restricted to tumors, methylation profile classes significantly predicted tumor type (P < 0.0001). Random forests classification of CpG methylation of tumors--which splits the data into training and test sets--accurately differentiated mesothelioma from lung adenocarcinoma over 99% of the time (P < 0.0001). In a locus-by-locus comparison of CpG methylation between tumor types, 1266 CpG loci had significantly different methylation between tumors following correction for multiple comparisons (Q < 0.05); 61% had higher methylation in adenocarcinoma. Using the CpG loci with significant differential methylation in a pathway analysis revealed significant enrichment of methylated gene-loci in Cell Cycle Regulation, DNA Damage Response, PTEN Signaling, and Apoptosis Signaling pathways in lung adenocarcinoma when compared with mesothelioma. Methylation profile-based differentiation of lung adenocarcinoma and mesothelioma is highly accurate, informs on the distinct etiologies of these diseases, and holds promise for clinical application.

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Figures

Figure 1
Figure 1. Unsupervised clustering heatmap of CpG loci in all samples and tumors only
Unsupervised hierarchical clustering heat map based on Manhattan distance and average linkage of the 500 autosomal CpG loci with the highest variance. Columns are samples, rows are CpG loci. Blue indicates methylated and yellow indicates unmethylated A) All samples, grey bars for mesotheliomas, red bars indicate lung adenocarcinomas, yellow bars are non-tumor lung samples, and pink bars are non-tumor pleura samples. B) Tumor samples only.
Figure 2
Figure 2. Recursively partitioned mixture model of CpG methylation for lung adenocarcinomas, mesotheliomas, and non-malignant pulmonary tissues
The figure depicts the results of RPMM. Columns represent CpG sites and rows represent methylation classes. The height of each row is proportional to the number of observations residing in the class, and the color of the columns within the row represents the average methylation of the CpG for that class. Blue indicates methylated and yellow indicates unmethylated. Pie charts represent the composition of the group of classes indicated with respect to tissue type. Methylation profile classes differentiate sample types (permutation test P < 0.0001).
Figure 3
Figure 3. Recursively partitioned mixture model of CpG methylation for lung adenocarcinomas and mesotheliomas
The figure depicts the results of RPMM. Columns represent CpG sites and rows represent methylation classes. The height of each row is proportional to the number of observations residing in the class, and the color of the columns within the row represents the average methylation of the CpG for that class. Blue indicates methylated and yellow indicates unmethylated. Pie charts represent the composition of the group of classes indicated with respect to tissue type. Methylation profile classes significantly differentiate tumor types (permutation test P < 0.0001).
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