An analysis of more than 100,000 colorectal cancer cases and 154,000 healthy controls published in Nature Genetics uncovered hundreds of signals that may serve as new treatment and prevention targets.
This study is twice as large as previous genome-wide association studies, according to the paper. The collaboration included researchers affiliated with hundreds of studies and institutions across Europe, North America and Asia, including Stephanie Schmit, PhD, MPH, Vice Chair of Cleveland Clinic’s Genomic Medicine Institute. Genome-wide association studies on this scale help researchers identify genes associated with colorectal cancer and also the biological pathways affected by those genes.
“This is a major stride in understanding the complexity of genetic susceptibility to colorectal cancer,” says Dr. Schmit, who first started working on part of this effort during her PhD training about a decade ago. “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.”
Dr. Schmit was among the group sharing first authorship on this study, representing the Colorectal Transdisciplinary Study (CORECT) funded by National Institutes of Health grant U19CA148107.
Colorectal cancer develops from growths, known as polyps, in the inner lining of the colon. The disease affects more than 1.9 million people worldwide annually. Though some rare mutations passed through families are associated with very high risk of colorectal cancer, but most of the genetic variants contributing to colorectal cancer are common in the population and each confer a very small increased risk on their own. Combined with environmental and lifestyle factors and cancer screening behaviors, genetics are one important piece of puzzle for this complex disease.
Researchers compared genomic data from people with and without colorectal cancer to identify genetic associations with the disease. The study identified 250 independent risk associations, 50 of which were previously undiscovered, through analyzing genomic, transcriptomic and methylomic data. The analyses also found 155 high-confidence effector genes, which encode molecules that affect biological activity.
Understanding the “complete picture” of colorectal cancer
After identifying the genes, researchers could then examine which risk-associated genes cause changes in other tissues outside of the colonic mucosa, the tissue lining the colon where cancerous polyps develop. The results showed more than a third of effector genes most likely act outside the colonic mucosa.
The study also found that colorectal cancer risk stems from variation in normal colorectal function on a molecular level: homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions.
The findings reveal that identified genes could affect multiple systems, including cardiovascular, nervous and immune functions. Gut microbiota is also a potential interest area for future research, according to the paper.
The new analysis and continued collaboration is a “springboard” for research efforts that could translate into clinical practice, Dr. Schmit says.
These discovery efforts help confirm which avenues to explore in colorectal cancer research moving forward. 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.”
Dr. Stephanie Schmit, PhD, MPH, Vice Chair of Cleveland Clinic’s Genomic Medicine Institute
Fernandez-Rozadilla, C., et al. (2022) Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries. Nature Genetics. doi.org/10.1038/s41588-022-01222-9.