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. 2009;4(3):e4941.
doi: 10.1371/journal.pone.0004941. Epub 2009 Mar 18.

Genome-wide hypomethylation in head and neck cancer is more pronounced in HPV-negative tumors and is associated with genomic instability

Kristy L Richards  1 , Baili Zhang, Keith A Baggerly, Stefano Colella, James C Lang, David E Schuller, Ralf Krahe
Affiliations

Genome-wide hypomethylation in head and neck cancer is more pronounced in HPV-negative tumors and is associated with genomic instability (V体育ios版)

Kristy L Richards et al. PLoS One. 2009.

Abstract

Loss of genome-wide methylation is a common feature of cancer, and the degree of hypomethylation has been correlated with genomic instability. Global methylation of repetitive elements possibly arose as a defense mechanism against parasitic DNA elements, including retrotransposons and viral pathogens. Given the alterations of global methylation in both viral infection and cancer, we examined genome-wide methylation levels in head and neck squamous cell carcinoma (HNSCC), a cancer causally associated with human papilloma virus (HPV). We assayed global hypomethylation levels in 26 HNSCC samples, compared with their matched normal adjacent tissue, using Pyrosequencing-based methylation assays for LINE repeats VSports手机版. In addition, we examined cell lines derived from a variety of solid tumors for LINE and SINE (Alu) repeats. The degree of LINE and Alu hypomethylation varied among different cancer cell lines. There was only moderate correlation between LINE and Alu methylation levels, with the range of variation in methylation levels being greater for the LINE elements. LINE hypomethylation was more pronounced in HPV-negative than in HPV-positive tumors. Moreover, genomic instability, as measured by genome-wide loss-of-heterozygosity (LOH) single nucleotide polymorphism (SNP) analysis, was greater in HNSCC samples with more pronounced LINE hypomethylation. Global hypomethylation was variable in HNSCC. Its correlation with both HPV status and degree of LOH as a surrogate for genomic instability may reflect alternative oncogenic pathways in HPV-positive versus HPV-negative tumors. .

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VSports在线直播 - Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Alu and LINE-1 methylation in a variety of tumor cell lines.
A. Alu methylation using the Alu-3 assay. B. LINE-1 methylation using the L1-3 assay. Results are reported as the PMR (percent methylated reference) normalized to the universally methylated reference DNA. Universally unmethylated (U2M), universally methylated (UM) controls, and normal control DNA from PBLs are also shown.
Figure 2
Figure 2. LINE-1 methylation in HNSCC tumor samples.
Paired tumor and normal samples and, where available, lymph node metastases were assayed for LINE-1 methylation. PMR values are plotted using the normal sample PMR as the x-value and primary tumor (circles) or metastasis (triangle) PMR as the y-value. Horizontal lines represent PMR values for universally methylation (UM) and unmethylated (U2M) controls, normal lymphocytes (green) and for four HNSCC cell lines (yellow). Box plots on the right show the mean and distribution of primary tumors and metastases in the subset of samples where matched metastases and primary tumors were available.
Figure 3
Figure 3. LINE-1 methylation levels are lower in HPV-negative HNSCC.
Box plots of methylation levels (PMR) of HNSCC primary tumors (right in each pair) and normal adjacent tissue (left in each pair) are shown according to HPV status. +/+, HPV-positive and expressing E6 viral mRNA; +/−, HPV-positive but transcriptionally silent; and −/−, HPV negative.
Figure 4
Figure 4. LINE-1 hypomethylation is correlated with degree of LOH in HNSCC.
LINE-1 methylation is plotted as PMR, and LOH is the fraction of 10K SNP loci that show LOH relative to all informative loci. Pearson correlation coefficient is −0.494 (p-value = 0.01) for the correlation between the two values.
See this image and copyright information in PMC

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