Discovery of genetic risk factors for colorectal cancer may help identify at-risk individuals

A comprehensive analysis of over 100,000 colorectal cancer (CRC) cases has identified over 100 new genetic risk factors strongly associated with this disease.

Led by researchers at Fred Hutchinson Cancer Center and conducted in collaboration with 200 scientific collaborators around the world, the results show that clinicians are most likely at risk for colorectal cancer. It may help to make better decisions about certain individuals and allow them to undergo early screening. The results may also help identify those who may benefit from prophylactic chemotherapy or other aggressive treatments.

“This is the largest and most comprehensive study to date of common genetic risk factors for colorectal cancer,” said Dr. Ulrike “Riki” Peters, molecular and genetic epidemiologist at Fred Hutch. . “We are thrilled with the findings of the study, which includes the addition of more than 100 genetic risk variants for this serious disease.” Peters was the study’s corresponding author, natural genetics,the title is”Decoding colorectal cancer genetics by multi-omics analysis of 100,204 cases and 154,587 controls of European and East Asian ancestryIn their paper, the team concludes, “These data significantly expand existing knowledge about the impact of common genetic variants on genetic risk for CRC.”

CRC affects approximately 1.9 million people worldwide each year and has a strong genetic basis, the authors wrote. “Our understanding of CRC genetics is informed by genome-wide association studies (GWAS) that have identified 150 statistically independent risk variants to date.” It focuses on genetic and environmental risk factors, as well as the impact of race and ethnicity on underlying genetic risk factors for common and complex diseases. The team’s previous research identified about 140 genetic markers for colorectal cancer.

For the newly reported study, researchers performed a meta-analysis of 100,204 colorectal cancer cases and 154,587 disease-free controls. Both groups were of European or Asian ancestry. “We complemented GWAS with transcriptome- and methylome-wide association analyzes (TWAS and MWAS),” the researchers added. Multi-omics is a biological analytical approach that combines multiple large-scale biological data sets ‘ohms’ such as genomes, proteomes and transcriptomes.

The initial findings of this study identified 205 independent risk associations for colorectal cancer, 50 of which were not previously reported. TWAS and MWAS revealed an additional 53 genetic variants associated with this disease. “Our study, which is twice as large as previous CRC GWAS, also included participants of both European and East Asian ancestry, suggesting that most loci are shared between these ancestral groups. “This enhanced power of GWAS, coupled with complementary analyzes such as TWAS and MWAS, identified 103 previously unreported risk associations and identified 155 effectors. genes have been identified.

Many of these high-confidence effector genes have been functionally linked to CRC risk and have hitherto had no established role in CRC. “They have multiple distinct functions, and we show that, among other things, alterations in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity, and microbial interactions determine CRC risk,” the scientists said. Dr. Li Hsu, co-first author and biostatistician at Fred Hatch, added:

Furthermore, the findings of this study validated more commonly known risk factors for CRC, such as insulin resistance, smoking and obesity, observed and reported in previous epidemiological studies.

Colorectal cancer is the leading cause of death worldwide. “Colorectal cancer is a serious disease, but it is preventable and can be successfully treated if detected early,” said Fred Hatch, director of the Gastrointestinal Cancer Prevention Program Clinic. Dr. William Grady, a professor at the university, said: “This research has the potential to pave the way for better screening and prevention, and could improve current methods of determining who is at higher risk.

“Germline genetic risk or genetic mutations (inherited from biological parents) play an important role in cancer risk and susceptibility.” Knowing who is at greatest risk can guide clinicians in recommending preventative measures and more frequent screening, potentially leading to earlier diagnosis and treatment and better patient survival outcomes. points out co-first author Minta Thomas. Fred Hatch’s Staff He is a scientist and works with Sue and Peters.

According to the study authors, their findings show the power of big data, combining such large-scale studies with complex, in-depth analysis using multi-omics to underlie colorectal cancer. Get more insight into biology. Researchers at Fred Hutch and collaborators are working to develop a germline DNA-based test that can classify individuals at high genetic risk for colorectal cancer from those who have a very small chance of developing the disease. , we plan to use the results in

The long-term goal is to combine genetic risk data with other risk factors (environmental, dietary, behavioral (e.g. smoking)) to create a multifaceted polygenic risk score that more accurately identifies a person’s colorectal cancer risk. is to create The authors conclude their paper by saying: Importantly, some of the genes and pathways we identified are potential targets for CRC therapy or chemoprevention. “