Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma

• Published in: Oncogene Vol. 29; no. 14; pp. 2104 - 2117
• Main Authors: Morris, M R, Ricketts, C, Gentle, D, Abdulrahman, M, Clarke, N, Brown, M, Kishida, T, Yao, M, Latif, F, Maher, E R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-04-2010; Nature Publishing Group
• Subjects: 631/67/581; 692/53/2422; 692/699/67/589/1588/1351; Adult; Aged; Apoptosis; Base Sequence; Biological and medical sciences; Biomarkers; Cancer; Carcinoma, Renal cell; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell Biology; Cell growth; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA Methylation; DNA microarrays; Epigenesis, Genetic; Epigenetics; Frizzled-related protein 1; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene Silencing; Genes, Tumor Suppressor; Genetic aspects; Human Genetics; Humans; Internal Medicine; Kidney cancer; Kidney diseases; Kidneys; Medical sciences; Medicine; Medicine & Public Health; Methylation; Middle Aged; Molecular and cellular biology; Molecular Sequence Data; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Prognosis; Renal cell carcinoma; RNA-mediated interference; Survival Analysis; Tumor cell lines; Tumor suppressor genes; Tumorigenesis; Tumors; Tumors of the urinary system; Young Adult; United Kingdom; renal cell carcinoma; methylation; epigenetics; Kidney disease; Urinary system disease; Carcinoma; Identification; Malignant tumor; Carcinogenesis; Epigenetics; Grawitz tumor; Candidate gene; Methylation; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.493

Promoter region hyermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many types of human cancers. Functional epigenetic studies, in which gene expression is induced by treatment with demethylating agents, may identify novel genes with tumour-specific methylation. We used high-density gene expression microarrays in a functional epigenetic study of 11 renal cell carcinoma (RCC) cell lines. Twenty-eight genes were then selected for analysis of promoter methylation status in cell lines and primary RCC. Eight genes (
BNC1
,
PDLIM4
,
RPRM
,
CST6
,
SFRP1
,
GREM1
,
COL14A1
and
COL15A1
) showed frequent (>30% of RCC tested) tumour-specific promoter region methylation. Hypermethylation was associated with transcriptional silencing. Re-expression of
BNC1
,
CST6
,
RPRM
and
SFRP1
suppressed the growth of RCC cell lines and RNA interference knock-down of
BNC1, SFRP1
and
COL14A1
increased the growth of RCC cell lines. Methylation of
BNC1
or
COL14A1
was associated with a poorer prognosis independent of tumour size, stage or grade. The identification of these epigenetically inactivated candidate RCC TSGs can provide insights into renal tumourigenesis and a basis for developing novel therapies and biomarkers for prognosis and detection.