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


CONCLUSIONS
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.
McRonald
Fiona E
FE
Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK. f.e.mcronald@bham.ac.uk
Morris
Mark R
MR
Gentle
Dean
D
Winchester
Laura
L
Baban
Dilair
D
Ragoussis
Jiannis
J
Clarke
Noel W
NW
Brown
Michael D
MD
Kishida
Takeshi
T
Yao
Masahiro
M
Latif
Farida
F
Maher
Eamonn R
ER
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016000:Cluster Analysis; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D016012:Poisson Distribution; D015203:Reproducibility of Results; D018709:Statistics, Nonparametric; D006623:von Hippel-Lindau Disease / Q000235:genetics*