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CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma.

McRonald FE, Morris MR, Gentle D, Winchester L, Baban D, Ragoussis J, Clarke NW, Brown MD, Kishida T, Yao M, Latif F, Maher ER - Mol. Cancer (2009)

Bottom Line: To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC). 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC.Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling.These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK. f.e.mcronald@bham.ac.uk

ABSTRACT

Background: Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC).

Results: 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling.

Conclusion: These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.

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Distribution of the number of genes found to be >25% methylated in each tumour, according to histological type. Poisson probabilities are based on the geometric mean of the total observed data (i.e. λ = 27.609) Geometric mean number of genes methylated for each tumour type is indicated by coloured circles on the x-axis.
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Figure 1: Distribution of the number of genes found to be >25% methylated in each tumour, according to histological type. Poisson probabilities are based on the geometric mean of the total observed data (i.e. λ = 27.609) Geometric mean number of genes methylated for each tumour type is indicated by coloured circles on the x-axis.

Mentions: The Illumina GoldenGate Methylation Cancer Panel I array provides quantitative CpG methylation data at 1505 individual CpG dinucleotides associated with 807 human genes. In order to profile patterns of RCC-specific candidate TSG methylation, we initially excluded 547 genes from further analysis because (a) they were methylated in Normal Kidney Tissue (NKT) (n = 338, this included X chromosome genes), (b) were methylated only in cell lines (n = 42), (c) were unmethylated in all samples studied (n = 101) or (d) a further 66 that fell into more than one of the above three categories (genes could be in >1 category as most genes had >1 CpG interrogated). 260 genes were methylated in tumour but not in NKT, and Euclidean cluster analysis was performed on these genes (see later). The number of methylated genes per individual tumour ranged between 4 and 117. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) (see figure 1). This suggested that the extent of methylation in individual tumours was not randomly distributed, and that a subset of RCC tumours might display CpG Island Methylator Phenotype (CIMP+ tumours) (see Figures 1 and 2).


CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma.

McRonald FE, Morris MR, Gentle D, Winchester L, Baban D, Ragoussis J, Clarke NW, Brown MD, Kishida T, Yao M, Latif F, Maher ER - Mol. Cancer (2009)

Distribution of the number of genes found to be >25% methylated in each tumour, according to histological type. Poisson probabilities are based on the geometric mean of the total observed data (i.e. λ = 27.609) Geometric mean number of genes methylated for each tumour type is indicated by coloured circles on the x-axis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698845&req=5

Figure 1: Distribution of the number of genes found to be >25% methylated in each tumour, according to histological type. Poisson probabilities are based on the geometric mean of the total observed data (i.e. λ = 27.609) Geometric mean number of genes methylated for each tumour type is indicated by coloured circles on the x-axis.
Mentions: The Illumina GoldenGate Methylation Cancer Panel I array provides quantitative CpG methylation data at 1505 individual CpG dinucleotides associated with 807 human genes. In order to profile patterns of RCC-specific candidate TSG methylation, we initially excluded 547 genes from further analysis because (a) they were methylated in Normal Kidney Tissue (NKT) (n = 338, this included X chromosome genes), (b) were methylated only in cell lines (n = 42), (c) were unmethylated in all samples studied (n = 101) or (d) a further 66 that fell into more than one of the above three categories (genes could be in >1 category as most genes had >1 CpG interrogated). 260 genes were methylated in tumour but not in NKT, and Euclidean cluster analysis was performed on these genes (see later). The number of methylated genes per individual tumour ranged between 4 and 117. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) (see figure 1). This suggested that the extent of methylation in individual tumours was not randomly distributed, and that a subset of RCC tumours might display CpG Island Methylator Phenotype (CIMP+ tumours) (see Figures 1 and 2).

Bottom Line: To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC). 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC.Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling.These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK. f.e.mcronald@bham.ac.uk

ABSTRACT

Background: Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC).

Results: 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling.

Conclusion: These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.

Show MeSH
Related in: MedlinePlus