One third of the most common forms of kidney cancer (clear cell renal cell carcinoma, ccRCC) involves a mutation of the same gene, called PBRM1, an international team of researchers wrote in in a leading journal this week.
Researchers from the Wellcome Trust Sanger Institute in the UK, the National Cancer Centre of Singapore, and Van Andel Research Institute (VARI) of Grand Rapids, Michigan, US, found that PBRM1 was mutated in 88 of 257 ccRCC cases they analysed, making it the most common mutation to be found in renal cancer in 20 years.
You can read about their findings in an online paper published on 19 January in Nature.
The discovery offers new insights into the intricate biology of renal cancer, revealing that the mutation in PBRM1, together with other already known mutations, appears to inactivate a protein that plays a role in remodelling the structure of genetic material.
For instance, it stops a protein that allows other proteins to access DNA in order to repair damage, control cell growth and switch other genes on and off.
The team has recently identified three mutated genes linked with renal cancer and discovered they are all involved in altering part of the chromatin “scaffold” that holds DNA together in our cells. Changes to chromatin can alter gene behaviour.
In this latest study they also found that PBRM1 is part of a protein complex called SWI-SNF, which regulates the structure of chromatin.
In the study report they explain how they:
” … sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1.”
This and the previous discoveries underline the importance of genome regulation in renal cancer, the researchers told the press.
As well as the PBRM1 mutation, the team also found some of the ccRCC cases had mutations in the ARID1A gene, which another recently published study revealed to be implicated in clear cell ovarian cancer. They said more research was needed to understand how this gene behaves in renal cancer.
According to figures from the National Cancer Institute, renal cancer is one of the ten most common cancers in men and women in the US, where last year nearly 60,000 people found out they had the disease and more than 13,000 died of it.
The most common type of renal cancer is renal cell carcinoma or RCC, accounting for 90 per cent of cases, and within this type ccRCC is the most common subtype, accounting for 80 per cent of RCC cases.
If diagnosed early, survival rates for ccRCC can reach 95 per cent, but this drops off as tumors develop, complicated by the fact that sometimes symptoms don’t show until a long time after tumors have started growing in the kidney.
Researchers have known for some time that the main genetic cause of RCC is a mutation in a tumor suppressor gene called VHL, located on chromosome 3. But this was not enough to explain the genetics of the disease: they knew there was more.
Dr Andy Futreal, Head of Cancer Genetics and Genomics and co-Head of the Cancer Genome Project at the Wellcome Trust Sanger Institute told the press that:
“Until recently, when we talked about the genetics of renal carcinoma we would inevitably be talking about VHL — a gene mutated in eight out of ten patients.”
“But we knew this was likely not to be the full story — so the question we have sought to answer is which genes are conspiring with VHL to cause the disease we see in patients?”
He explained the team has been trying to solve the puzzle for the last twelve months, and this study reveals a crucial new piece.
Professor Mike Stratton, Director of the Sanger Institute and co-Head of the Cancer Genome Project said that the previous finding of the mutated genes has greatly improved our understanding of how kidney cancer develops.
“Now, our discovery of PBRM1 mutations in one in three kidney cancers is a major advance,” he added.
“We think we may have an almost complete understanding of the set of abnormal genes that drive this cancer and our understanding of the disease has been transformed by the realisation that most of these genes are involved in providing the structure that encases DNA in the cell and that regulates its function,” he explained.
Stratton thinks this latest discovery will give drug researchers many new directions in which to pursue new treatments.
Much of the story is centred around a small region of chromosome 3: home to the well-established VHL cancer gene and the recently identified gene SETD2, and now, with this latest discovery, a third gene, PBRM1(also known as Baf180).
The team suggests that the co-location of the three genes gives the cancer a chance to exploit our biology by reducing the number of genetic events needed to render the genes inactive.
In this study they found significant co-existence of mutations in cancer cases, with some patients carrying mutations in two, if not all three of these co-located genes.
Professor Bin Tean Teh, Head of the Van Andel Research Institute Laboratory for Cancer Genetics and the NCSS-VARI Translational Research Laboratory at the National Cancer Centre of Singapore, said:
“This study has begun to unlock the way these latest gene discoveries contribute to cancer.”
He said the fact the genes are co-located gives the cancer an advantage and the challenge now is to find out which processes these genes control.
“That will mean looking beyond the linear DNA code to the chemical interactions that take place at the structural level — at the level of the chromosome,” he added.
“Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.”
Ignacio Varela, Patrick Tarpey, Keiran Raine, Dachuan Huang, Choon Kiat Ong, Philip Stephens, Helen Davies, David Jones, Meng-Lay Lin, Jon Teague, et al.
DOI:10.1038/nature09639
Additional source: Van Andel Research Institute (press release, 19 Jan 2011).
Written by: Catharine Paddock, PhD