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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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Most significant gene networks for genes more methylated in papillary RCC than clear cell RCC. Genes in unfilled nodes were not identified as specifically methylated in tumours (TGF-β, AKT, PDGFB) or were not represented on the array (ITGA8, ITGA10, ITGA11, PEBP4, ERK, SLC12A4, JNK, ITGB1BP2, CDO1, NCK1, NLK, PI3K, CNN2, FSD1, SLC7A8, ELOVL2, FXYD5, PDGFD and PDAP1. The computationally generated networks were derived using the Ingenuity package . (see Figure 6 for key to nodal shape).
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Figure 4: Most significant gene networks for genes more methylated in papillary RCC than clear cell RCC. Genes in unfilled nodes were not identified as specifically methylated in tumours (TGF-β, AKT, PDGFB) or were not represented on the array (ITGA8, ITGA10, ITGA11, PEBP4, ERK, SLC12A4, JNK, ITGB1BP2, CDO1, NCK1, NLK, PI3K, CNN2, FSD1, SLC7A8, ELOVL2, FXYD5, PDGFD and PDAP1. The computationally generated networks were derived using the Ingenuity package . (see Figure 6 for key to nodal shape).

Mentions: To determine if differential CpG methylation patterns in RCC might relate to preferential targeting of specific signalling pathways, the Ingenuity functional annotation pathway was utilised. 8/14 genes that were significantly more methylated in pRCC than cRCC were represented in a network with links to TGFβ and ERK/Akt pathways (see Figure 4). The link to these pathways was more pronounced (9/12) for those 12 genes that were more frequently methylated in pRCC than in wtVHL-cRCC (see Figure 5 (see figure 6 for key to nodal shape in figures 4 and 5). The 18 genes that were methylated in all NKT samples but <72% of renal tumours did not demonstrate a significant association with a particular pathway.


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)

Most significant gene networks for genes more methylated in papillary RCC than clear cell RCC. Genes in unfilled nodes were not identified as specifically methylated in tumours (TGF-β, AKT, PDGFB) or were not represented on the array (ITGA8, ITGA10, ITGA11, PEBP4, ERK, SLC12A4, JNK, ITGB1BP2, CDO1, NCK1, NLK, PI3K, CNN2, FSD1, SLC7A8, ELOVL2, FXYD5, PDGFD and PDAP1. The computationally generated networks were derived using the Ingenuity package . (see Figure 6 for key to nodal shape).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Most significant gene networks for genes more methylated in papillary RCC than clear cell RCC. Genes in unfilled nodes were not identified as specifically methylated in tumours (TGF-β, AKT, PDGFB) or were not represented on the array (ITGA8, ITGA10, ITGA11, PEBP4, ERK, SLC12A4, JNK, ITGB1BP2, CDO1, NCK1, NLK, PI3K, CNN2, FSD1, SLC7A8, ELOVL2, FXYD5, PDGFD and PDAP1. The computationally generated networks were derived using the Ingenuity package . (see Figure 6 for key to nodal shape).
Mentions: To determine if differential CpG methylation patterns in RCC might relate to preferential targeting of specific signalling pathways, the Ingenuity functional annotation pathway was utilised. 8/14 genes that were significantly more methylated in pRCC than cRCC were represented in a network with links to TGFβ and ERK/Akt pathways (see Figure 4). The link to these pathways was more pronounced (9/12) for those 12 genes that were more frequently methylated in pRCC than in wtVHL-cRCC (see Figure 5 (see figure 6 for key to nodal shape in figures 4 and 5). The 18 genes that were methylated in all NKT samples but <72% of renal tumours did not demonstrate a significant association with a particular pathway.

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