Genetic Research on Colorectal Cancer Risk

Overview of Colorectal Cancer

Researchers in the United States have analyzed the genomes of over 125,000 individuals to identify genetic variants linked to an increased risk of colorectal cancer, a significant cause of mortality worldwide. This type of cancer originates in the large intestine, which includes the colon and rectum. Abnormal changes in the cells of these areas can lead to tumor formation, which may progress to cancer and spread to other body parts. The risk of developing colorectal cancer rises with age, prompting medical professionals to recommend routine screenings for individuals over 50. Additionally, a family history of colorectal cancer and certain genetic predispositions can elevate the risk.

Understanding Genetic Variants

Genetic variants are minor differences in DNA sequences among individuals. These variants may occur within genes, which are responsible for protein coding, or in the non-coding regions of DNA. Although many genetic variants do not manifest in noticeable physical traits or health issues, some can increase susceptibility to diseases like cancer by disrupting gene function or altering gene expression levels. This can make cells more vulnerable to early cancerous changes.

Genome-Wide Association Studies (GWAS)

To identify genetic variants associated with diseases, researchers often utilize genome-wide association studies (GWAS). These studies analyze various genetic variants in both affected individuals and controls, allowing scientists to determine which variants are more prevalent in those with the disease.

Investigating Genetic Risk Factors for Colorectal Cancer

Previous Discoveries

Earlier studies have discovered 55 genetic variants linked to a heightened risk of colorectal cancer. However, these variants explain only a small percentage of cases among patients with a family history of the disease, indicating that additional genetic factors remain to be identified.

Recent Study Findings

A recent study published in *Nature Genetics* by researchers at the Fred Hutchinson Cancer Research Center aimed to uncover further genetic variants associated with colorectal cancer. By utilizing genetic data from nearly double the sample size of previous GWAS studies—more than 125,000 individuals—the researchers were able to identify rare genetic variants previously overlooked.

The researchers sequenced the genomes of 1,439 colorectal cancer patients and 720 controls, integrating this data with genome sequences from 45 additional studies, including those from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. The final analysis included genome sequences from 59,570 individuals with colorectal cancer and 68,067 controls.

Newly Identified Variants

Through their research, the team identified 40 new genetic variants linked to an increased risk of colorectal cancer. Notably, many of these variants are located near previously recognized variants on the genome or are involved in similar biological processes. Moreover, many of these new variants are situated in regulatory elements—DNA sequences that influence the expression levels of nearby genes, rather than in protein-coding genes.

Interestingly, the researchers also discovered a rare variant within the CHD1 gene, which appears to confer a protective effect against colorectal cancer. Individuals carrying this variant exhibited a lower incidence of the disease.

Implications for Disease Prevention

Significance of Genetic Knowledge

Understanding which genetic variants influence an individual’s risk for colorectal cancer is crucial for prevention strategies. Identifying high-risk variants can prompt earlier genetic testing and screening for individuals predisposed to developing the disease.

Despite uncovering numerous genetic variants associated with increased colorectal cancer risk, many factors remain unidentified. The previously recognized 55 variants accounted for only 8.8% of colorectal cancer patients with a family history. The addition of the 40 new variants from this study raises that percentage to only 11.2%.

Study Limitations and Future Research

One limitation of this study is its demographic composition, as the majority of participants (91.7%) were of European ancestry, with only 8.3% from East Asian backgrounds. Future research will aim to include a more diverse range of ethnic groups to identify additional genetic variants affecting colorectal cancer risk in non-European populations.

Reference

Huyghe JR, Bien SA, Harrison TA, et al. Discovery of common and rare genetic risk variants for colorectal cancer. 2018. Nat Genet DOI:10.1038/s41588-018-0286-6