colorectal cancer risk
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Researchers in the United States examined the genomes of over 125,000 people to identify genetic variants associated with increased colorectal cancer risk.

Colorectal cancer is one of the deadliest cancers worldwide. Colorectal cancer starts from cells in the large intestine, comprised of the colon and rectum. These cells may stop functioning normally and start to multiply faster than normal, leading to the development of tumours. These tumours may eventually become cancerous and able to spread to other parts of the body.

Colorectal cancer risk increases with age, which is why doctors recommend routine screening for signs of tumours in the rectum and colon for those over 50. However, a family history of colorectal cancer and other genetic factors can also increase the risk of developing colorectal cancer.

Genetic variants and disease

Genetic variants are small differences in a specific DNA sequence among different people. Genetic variants may be in genes, which are segments of DNA that code for a protein to be produced, or in the DNA between genes. These variants can occur anywhere in the genome, which is the entire set of DNA sequences present in each cell.

Many genetic variants do not lead to any obvious effects on our appearance, how our body functions, etc. However, some genetic variants put people at a higher risk of developing diseases such as cancer. Variants can hinder the function of a gene or cause a gene to be expressed too much or not enough. As a result, cells may be prone to changes that occur early in the development of cancer.

Many researchers have searched for genetic variants that increase colorectal cancer risk. To find genetic variants associated with a disease, researchers often use genome-wide association studies (GWAS). GWAS examine many different genetic variants across the genome in people with the disease and people without the disease. Researchers then determine what variants are present in people with the disease much more often than in people who do not have the disease.

A search for genetic risk factors for colorectal cancer

Previous studies identified 55 genetic variants associated with an increased risk of developing colorectal cancer. However, these variants only account for a small fraction of patients with a family history of colorectal cancer, meaning there are many more genetic factors to be uncovered.

In a study recently published in Nature Genetics conducted at the Fred Hutchinson Cancer Research Center in the United States, researchers performed a GWAS to uncover additional genetic variants that increase colorectal cancer risk. These researchers used genetic data from more than 125,000 individuals, which is nearly double the sample size of previous GWAS studies on the subject. This large sample size helped them extract rare genetic variants that were not identified in previous studies.

Researchers sequenced the genomes of 1,439 people with colorectal cancer and 720 people without colorectal cancer (controls). They pooled this data with genome sequences from 45 other studies from the Genetics and Epidemiology of Colorectal Cancer Consortium, the Colorectal Cancer Transdisciplinary Study, and the Colon Cancer Family Registry. In total, they examined genome sequences from 59,570 people with colorectal cancer and 68,067 controls.

New variants associated with altered risk of colorectal cancer

Researchers identified 40 new variants associated with increased colorectal cancer risk. Many of these new variants are close to previously identified variants on the genome, or function in the same processes as previously identified variants.

The researchers also found that many of these new variants are not in genes that encode proteins but in regulatory elements. Regulatory elements are DNA sequences near genes that affect how much a nearby gene or set of genes gets expressed.

Remarkably, the researchers also identified a rare variant that seems to have a protective effect against colorectal cancer. Participants with this variant in the gene CHD1, which affects how DNA is packaged in the nucleus, had a lower incidence of colorectal cancer.

Important knowledge for disease prevention

Knowing what genetic variants affect a person’s risk of developing a disease is important for disease prevention. If we know what variants put people at a higher risk of developing colorectal cancer, genetic testing earlier in life can inform those at higher risk that they need to start routine screening earlier.

Though this screen identified many more genetic variants that increase colorectal cancer risk, there are still many genetic factors that remain undiscovered. The previously identified 55 genetic variants only accounted for 8.8% of colorectal cancer patients with a family history of the disease. With the addition of the 40 genetic variants identified in this study, still, only 11.2% of these familial cases of colorectal cancer are accounted for.

One limitation of this study is that the individuals used were mostly of European ancestry (91.7% European ancestry, 8.3% East Asian ancestry). Continued research will include participants from more diverse ethnic backgrounds to uncover additional genetic variants that affect colorectal cancer risk that are present in people of non-European ancestry.

Written by Melissa H. Wong, MSc

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

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