Study highlights how a key genetic variant could confer colorectal cancer risk

Heritable genetic variation has been found to contribute to more than a third of overall colorectal cancer risk.

Previous studies from the group have highlighted how variation in a specific region, 11q23.1 of human chromosome 11, imparts risk of developing colorectal cancer (CRC). 

This area influences the functioning of several genes, including POU2AF2, COLCA1, and POU2AF3, but their complicated interaction has made it difficult for scientists to determine exactly how changes in their expression contribute to the risk of developing CRC.

Using a variety of techniques, including analysis of RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation sequencing and single-cell ATAC sequencing data, the researchers set out to identify, prioritise and characterise the genes that contribute to CRC risk. 

The study highlighted a genetic variant known as rs3087967 as being particularly influential within the 11q23.1 region. This variant influences the expression of 21 other genes located in different parts of the genome, significantly influencing their activity. Most notably, rs3087967 affects the expression of POU2AF2 which is linked with tuft cells, a type of cell in the lining of the colon which is now believed to play a critical role in preventing tumour development in this part of the body.

Using a technique called immunofluorescence, the researchers found that a specific version of rs3087967, the risk genotype ('T'), was associated with a tuft cell deficit in the human colon. Deleting this genetic region exacerbated cancer development, highlighting its protective role against tumours.

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