Genomic research reveals new mutations in kidney cancer
7 January 2010
Clear cell renal cell carcinoma (ccRCC) causes 102 000 deaths worldwide each year. The majority of cases are known to be driven, at least in part, by mutations in a single gene, VHL.
By sequencing thousands of genes from over 100 cases of ccRCC, researchers from the Wellcome Trust Sanger Insitute found VHL mutations in more than half of the cases examined, but also additional mutations in other genes.
In particular, they showed that two genes that help control gene expression on a genome-wide level had been inactivated by mutations. The genes JARID1C and SETD2 produce proteins that help how DNA is packaged, which affects the activity of genes.
"This study has uncovered abnormalities in genes that encode the machinery determining the structure of chromatin - the three-dimensional environment of proteins that hold DNA," said Professor Mike Stratton, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute.
"This machinery is critical to the fine regulation of transcription of genes into RNA and therefore to the functioning of all cells. We have now shown that several components of the machinery are mutated in cancer and the consequent abnormalities in their function contribute to the development of the disease."
The researchers also identified mutations in the gene NF2 in a particular subset of ccRCCs that appear to not be driven by mutation in VHL. The NF2 gene is known to be involved in hereditary cancers affecting primarily the nervous system.
The researchers looked for mutations in 3544 genes in 101 cases of ccRCC - the largest number of samples from a single tumour type to be sequenced to date.
They noted that none of the additional mutations found accounted for more than five per cent of cases, showing how complex human cancer can be.
However, their findings mean that even cancers that seem to have a similar cause - such as ccRCC and the VHL mutations - can be further classified into subtypes that display distinctive biological features driven by specific mutations. This will ultimately enable more accurate diagnosis and selection of treatments.
Last month, researchers from the Sanger Institute announced the first detailed search of breast cancer genomes characterising human genome rearrangements in 24 cases of breast cancer. They also announced the sequencing of lung and melanoma cancers, the first comprehensive analyses of cancer genomes completed.
Image: High magnification micrograph of a clear cell renal cell carcinoma. Credit: Bin Teh, Van Andel Research Institute
Reference
Dalgliesh GL et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 2010 [Epub ahead of print]
