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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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Related in: MedlinePlus

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.
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pone-0004941-g002: 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.

Mentions: Matching normal, primary tumor, and where available, lymph node metastases of head and neck patient samples (Table S1) were tested using our PMA LINE-1 assays (Figure 2). Because of the greater dynamic range of the LINE-1 assay and limited sample amounts, only LINE-1 assays were performed for the remainder of this study. In general, HNSCC primary tumors and metastatic lymph nodes were hypomethylated compared to their matching normal adjacent tissues. With the LINE1-1 assay, the mean primary tumor PMR was 65.5%, while the mean normal PMR was 90.0% (p-value = 6.7×10−8 using a paired t-test). However, there was quite a bit of variability in the primary tumors, ranging from 31.2% (severe hypomethylation) to 90.8% (normal). The mean PMR in lymph node metastases (73.8%; range 31.8%–93.8%) was also highly variable, even with respect to the corresponding primary tumor, sometimes lower and sometimes higher than the PMR of the primary tumor with which it is associated.


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 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.
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Related In: Results  -  Collection

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

pone-0004941-g002: 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.
Mentions: Matching normal, primary tumor, and where available, lymph node metastases of head and neck patient samples (Table S1) were tested using our PMA LINE-1 assays (Figure 2). Because of the greater dynamic range of the LINE-1 assay and limited sample amounts, only LINE-1 assays were performed for the remainder of this study. In general, HNSCC primary tumors and metastatic lymph nodes were hypomethylated compared to their matching normal adjacent tissues. With the LINE1-1 assay, the mean primary tumor PMR was 65.5%, while the mean normal PMR was 90.0% (p-value = 6.7×10−8 using a paired t-test). However, there was quite a bit of variability in the primary tumors, ranging from 31.2% (severe hypomethylation) to 90.8% (normal). The mean PMR in lymph node metastases (73.8%; range 31.8%–93.8%) was also highly variable, even with respect to the corresponding primary tumor, sometimes lower and sometimes higher than the PMR of the primary tumor with which it is associated.

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