European researchers identify more genes responsible for cancer

A European team of researchers has successfully identified hundreds of genes responsible for the development of cancer, by examining the DNA of more than 500 lymphomas – cancers that develop in
lymphatic cells – the researchers discovered 10,806 mutations.

The findings were recently published in the journal Cell.

Nearly 350 regions in the mouse genome are involved in the formation of cancer, the results show. The researchers say that of these regions, 50 are consistent with genes that play a role in
cancers found in humans, while the remaining 250 regions are new.

Headed by researchers from the Netherlands Cancer Institute (NKI) and the UK-based Wellcome Trust Sanger Institute, the consortium generated mutations in cancer genes by using the so-called
‘murine leukaemia’ virus. This virus hones in on white blood cells, causing lymphomas (cancerous tumours).

‘Human cancers are generally thought to be formed by the stepwise accumulation of mutations that disrupt genes within a cell, and the virus mimics this process as it inserts itself into the
mouse genome,’ says Dr David Adams of the Wellcome Trust Sanger Institute, and the study’s lead author. ‘The virus then acts as a ‘tag’, allowing us to identify where it has integrated and
which gene or genes have been disrupted,’ he explains.

‘By finding an average of 20 mutations from each of the 500 tumours, not only did we find many new cancer genes, but we can see which genes work together in the same cell to transform it into a
lymphoma,’ says co-author Dr Jaap Kool from the NKI.

According to the researchers, the genes p53 and p19 were the hosts for the mutations found in the infected mouse lines. The p53 gene has many anti-cancer mechanisms, including being able to
activate DNA repair proteins when DNA has sustained damage.

Previous research has shown that when the p53 is mutated, it contributes to the transformation of healthy cells to cancerous cells because it switches off genes that typically stop new cell
growth. The p19 gene is key because it prevents the breakdown of the p53 gene’s protein. The body can then suppress cell growth and inhibit the formation of a tumour.

The researchers involved in the latest study identified a rich set of novel genes implicated in cancer, which were not easily observed in other studies. An example of such genes are those with
the potential to suppress tumour development.

Human cancer cells frequently contain many mutations that are not involved in the development of cancer – do not drive cancer development – but are produced by increased mutation rates in
cancer cells and are ‘passengers’. The challenge for human cancer gene studies, say the researchers, is determining the ‘driver’ and ‘passenger’ mutations.

‘The benefit of our system in the mouse is that, unlike human tumours, which usually contain many different types of genetic alternations, the causal mutations that initiate these tumours in
mice can be easily identified and studied,’ explains Dr Adams. ‘These studies are complementary to and enrich the analysis of human cancers.’

High-throughput sequencing and computational resources found at the Sanger Institute were used in the study, effectively providing the researchers with the means to identify new potential
cancer genes in the mouse. They then compared their data with genome-wide human cancer datasets that were produced by the Cancer Genome project at the Sanger Institute. Through this work, the
researchers were able to shed light on how the identified genes could prove significant in the formation of human cancer.

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