Large Genome-Wide Association Study Finds Possible New Colorectal Cancer Targets

The largest genome-wide association study to date in colorectal cancer (CRC) discovered hundreds of genes linked to CRC risk among a diverse population of both European and Asian ancestry. Findings were published in Nature Genetics.

This study is important because it sheds light on areas of CRC that needs to be further examined to identify genetic risks associated with the disease and then develop appropriate screenings and chemoprevention approaches for patients with these high-risk factors.

“This is a major stride in understanding the complexity of genetic susceptibility to colorectal cancer,” Stephanie Schmit, PhD, MPH, vice chair of Cleveland Clinic’s Genomic Medicine Institute, said in a statement. “The data uncovered some pathways that could hold potential for prevention and treatment of the disease and provide continued reinforcement of exploring mechanisms outside of the colon, such as the immune system.”

CRC is the leading cause of mortality worldwide and affects 1.9 million people each year. CRC is known to develop from polyps in the inner lining of the colon. However, rare forms of mutations that result in high-risk CRC can be passed down through families by genetics. Futhermore, these risk-associated genes can cause changes in areas of the body other than the colon lining.

This study included data from more than 100,000 CRC cases and 154,000 healthy controls from institutions across Europe, North America, and Asia (73% European ancestry, 27% east Asian ancestry), making it twice as large as previous genome-wide association studies.

Using tissue-specific gene expression and other data types, the researchers compared genomic data from individuals with and without CRC and identified 205 independent risk associations, of which 50 had not yet been discovered. Transcriptome- and methylome-wide association studies further revealed 53 risk associations. The researchers were also able to identify 155 high-confidence effector genes, which affect biological activity.

Using cross-tissue analysis, the researchers found that more than one-third of effector genes acted outside of the colon lining, potentially affecting other systems in the body, such as the cardiovascular, nervous, and immune systems.

For instance, genes such as HIVEP1, LIF, SH2B3, TOX, and TOX4 were found to influence the development of CRC through immune cell variation, whereas EDNRB influences risk through effects on blood vessels.

The researchers also unexpectedly found several effector genes that had primary roles in neurogenesis, suggesting that the enteric nervous system may play a part in CRC risk development.

The availability of multi-omic data sets is crucial in order to further understand how specific genes may increase or indicate risk of CRC among different populations worldwide.

“These discovery efforts help confirm which avenues to explore in colorectal cancer research moving forward,” Schmit said in the statement. “The additional data on biological pathways provide information for discerning genetic risk for colorectal cancer and how these insights could potentially be leveraged for risk-stratified screening and for the development of new prevention and treatment approaches.”

Reference

Fernandez-Rozadilla C, Timofeeva M, Chen Z, et al. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and East Asian ancestries. Nat Genet. Published online December 21, 2022. doi:10.1038/s41588-022-01222-9