Genetics and stem cells

Genetic clue to kidney cancer

A faulty gene has been linked to more than a third of all kidney cancers, The Daily Telegraph has reported. The newspaper says that the discovery may help researchers understand the development of kidney cancer, and potentially lead to new treatments and diagnosis methods.

The news is based on research that found that mutations in a gene called PBRM1 were present in 88 out of 257 patients with renal cell carcinomas, the form that accounts for 90% of kidney cancers. If developed, a genetic test could be of major benefit as early diagnosis greatly increases the long-term survival rate for the condition, which falls once the cancer begins to spread.

Combining this new knowledge with what we already know about other kidney cancer mutations (particularly of the tumour-suppressing VHL gene, which is mutated in 80% of patients) provides a better picture of how the cancer develops. In time this may lead to new diagnostic tests for the disease and drugs designed to act in relation to these mutations. However, this information is only the first step towards these goals, and work in this area may take some time.

Where did the story come from?

The study was led by researchers from the Cancer Genome Project at the Wellcome Trust Sanger Institute in the UK. Several other laboratories across the world contributed, and the study was supported by grants and fellowships form the Wellcome Trust, Cancer Research UK and a number of other organisations. The study was published in the peer-reviewed journal, Nature.

The BBC and The Daily Telegraph have reported the study accurately, emphasising that the research has discovered a link between a genetic mutation and kidney cancer, rather than a cause of the condition. While there is clearly more work to be done in this field, news sources are justified in reporting that this discovery is a major advance. The Telegraph also rightly states that the exact reason why the gene is damaged or inactivated has not yet been established.

What kind of research was this?

The researchers explain that, in previous renal cancer genetic studies, inactivation of the VHL gene seemed to lead to imbalance in the proteins within cells, which in turn leads to a common type of kidney cancer called “renal clear cell adenocarcinoma” (ccRCC). However, previous experiments have shown that loss of VHL is not sufficient to cause ccRCC tumours, which suggests that other genes may play a role in this cancer.

Previous research has discovered that a range of other genes control how DNA is “read” and copied in the first stages of making a proteins, but the researchers say that these identified genes are together found in 15% of ccRCC patients. They say that they have found a similar type of “control gene” called the PBRM1 gene, and set out to see how many patients with renal cancer carry mutations of this newly implicated gene and what type of mutations these were.

DNA is divided into two types of sequences:

  • “exons”, which contain the DNA sequences used to manufacture proteins
  • “introns”, which are sequences of DNA that lie between the exon coding sequences but do not themselves code for proteins

The researchers looked for genes that may be involved in kidney cancer using a technique called “exome sequencing”, which concentrates on the genetic sequences found only in exons. The researchers say that this is an efficient strategy. These protein-coding regions constitute only about 1% of the human genome and because these protein-coding exons are thought to contain about 85% of disease-causing mutations.

What did the research involve?

The study featured several phases and applied established techniques to examine DNA samples obtained from patients with kidney tumours and matching (unaffected) controls. The researchers used samples from 257 patients that had ccRCC and 36 patients with other types of renal cancer.

To obtain further support that PBRM1 can act as a cancer gene, they also used genetic material from mouse pancreatic cancer to investigate how the gene could be turned on and off.

To investigate the effects of PBRM1 mutations the researchers used a technique called “small interfering RNA (SiRNA) knockdown”, which uses small pieces of genetic material to disrupt the actions of certain genes. They used this method to switch off the PBRM1 gene in renal carcinoma cells to see whether this affected how fast they divided and grew.

They also looked at the gene PBRM1 specifically and in detail, looking to see what type of mutation had occurred in the renal cancer cells.

What were the basic results?

In the sequencing phase of the study, the researchers identified “truncating mutations” of the PBRM1 gene within 34% (88/257) of the renal cancer cases. A truncating mutation within a gene will cause it to produce a shortened or abnormally structured version of the protein it should normally produce, usually leaving that protein unable fulfil its intended function. When they looked at the action of this PBRM1 mutation, it was found to produce a shorter version of the normal protein.

The researchers found that when they switched off the PBRM1 gene with the knockdown technique, the renal cancer cells divided more quickly. This suggests that the normal PBRM1 protein may have a role as a tumour suppressor.

How did the researchers interpret the results?

The researchers say that their identification of a second major cancer gene in this type of kidney cancer further defines this tumour type. They say that a better understanding of how PBRM1 mutation leads to clinical disease progression and outcomes for patients will be an important future area for renal cancer research.


This well-conducted international study applied a range of relevant approaches and the work of numerous researchers from several different institutions, which adds to the confidence in the results. Although the underlying genetic and molecular biology may be complex, the progress being made in this field, and for this cancer in particular, does offer hope for new diagnostic tests that may help in targeting new treatments. 

This was early research, and as such considerably more work is needed before any related genetic test could be used on a wider scale. It is not clear how long this might take. It would also be necessary to look for the prevalence of the mutation in a larger sample of kidney cancer patients.

NHS Attribution