In the past, many researchers worldwide aimed at identifying cancer-causing genes, meaning those genes that are relevant for tumour progression and cell malignancy, where a mutation in a particular gene makes the difference in cancer.

So, most of the cancer genomics research has been focused in the role of positive selection, which is the evolutionary mechanism promoting mutations in those cancer driver genes.

On the other hand, the existence of detectable levels of negative selection in cancer genomes is being questioned by several studies. Negative selection is the opposite type of natural selection promoting stability and preventing the accumulation of harmful mutations.

Even though it is a major force in species evolution, experimental and computational methods attributed only a limited role to negative selection in cancer.

Now, a team of scientists at the Centre for Genomic Regulation (CRG) in Spain, have developed a new method to identify genes under negative selection.

Their results, published inGenome Biology,  challenge the most extended paradigm of an exclusive role of positive selection in cancer evolution.

“We found that negative selection plays an important role in cancer evolution, which is quite controversial because it has been historically neglected in most studies and, ultimately, challenges the current paradigm of an exclusive role of positive selection in cancer,” explains Dr.  Martin Schaefer, scientist at the Design of Biological Systems Laboratory, who led the study. 

The researchers analysed more than 7,500 individual functional genomes (exomes) from 26 tumour types from The Cancer Genome Atlas (TCGA) data, and identified essential cancer genes and immune-exposed protein regions under significant negative selection.

“This is the first large scale study with a solid method to detect a substantial impact of negative selection in shaping cancer genomes. We demonstrate that negative selection is underestimated and acts stronger on certain regions, which are related to essential cellular functions and to immune response,” adds Schaefer.

“Our work could be interpreted as a proof of concept; it may shed light upon mechanisms underlying immune evasion and may provide insights for improving cancer therapies in the future by revealing cancer vulnerabilities”.


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