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

Richards KL, Zhang B, Baggerly KA, Colella S, Lang JC, Schuller DE, Krahe R - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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. 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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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.
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pone-0004941-g004: 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.

Mentions: Colon cancer cell lines with more pronounced LINE hypomethylation were previously reported to have a higher degree of LOH [14], [15]. To examine whether this correlation held true in our HNSCC patient samples, we performed a global LOH analysis using 10K SNPChip data. Genotypes were compared between normal adjacent tissue and matched tumor samples; informative loci were those that were heterozygous in the normal tissue. Figure 4 shows a plot of the percentage of informative loci for each primary tumor with LOH versus the degree of LINE-1 methylation in the same specimen. We fit a linear trend to the data, which showed a Pearson correlation of −0.494, with a p-value = 0.017. As a check of robustness, we also calculated the Spearman (rank-based) correlation, which was also significant. The Spearman correlation coefficient for this relationship was −0.428 (p-value = 0.042), establishing that LOH was indeed significantly correlated with the degree of LINE hypomethylation.


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

Richards KL, Zhang B, Baggerly KA, Colella S, Lang JC, Schuller DE, Krahe R - PLoS ONE (2009)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654169&req=5

pone-0004941-g004: 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.
Mentions: Colon cancer cell lines with more pronounced LINE hypomethylation were previously reported to have a higher degree of LOH [14], [15]. To examine whether this correlation held true in our HNSCC patient samples, we performed a global LOH analysis using 10K SNPChip data. Genotypes were compared between normal adjacent tissue and matched tumor samples; informative loci were those that were heterozygous in the normal tissue. Figure 4 shows a plot of the percentage of informative loci for each primary tumor with LOH versus the degree of LINE-1 methylation in the same specimen. We fit a linear trend to the data, which showed a Pearson correlation of −0.494, with a p-value = 0.017. As a check of robustness, we also calculated the Spearman (rank-based) correlation, which was also significant. The Spearman correlation coefficient for this relationship was −0.428 (p-value = 0.042), establishing that LOH was indeed significantly correlated with the degree of LINE hypomethylation.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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. 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.

Show MeSH
Related in: MedlinePlus