Researchers at the Fred Hutchinson Cancer Center, conducting a broad, comprehensive analysis of more than 100,000 cases of colorectal cancer (CRC) have identified 100-plus new genetic risk factors strongly linked with the disease.
The findings, published in Nature Genetics, demonstrating the power of using big data—combining a large-scale study with complex, detailed analysis using multi-omics —to gain additional insights into the underlying biology of colorectal cancer. The researchers also said their data could be used as the basis to develop early screening strategies to identify at-risk patients, while also potentially suggesting the best treatment options for those diagnosed with CRC.
“This is the largest, most comprehensive study to date of common genetic risk factors for colorectal cancer,” said Ulrike “Riki” Peters, PhD, a molecular and genetic epidemiologist at Fred Hutchinson and lead author of the study. “We’re excited about our study’s discoveries, including the addition of 100-plus genetic risk variants for this severe disease.”
The new research sought to add to the body of knowledge about CRC, which to date has identified 150 statistically independent risk variants via genome-wide association studies (GWAS). For this study, Peters and more than 200 colleagues at a range of research centers focused on the genetic and environmental risk factors for CRC, and included the impact of race and ethnicity on underlying genetic risk factors for common, complex diseases. The team’s previous work had identified about 140 genetic markers for colorectal cancer.
The investigators conducted a meta-analysis of 100,204 colorectal cancer cases and 154,587 controls without the disease. Both groups were of European or Asian ancestry. “We complemented GWASs with transcriptome- and methylome-wide association analyses (TWASs and MWASs),” the researchers wrote.
The study’s initial findings identified 205 independent risk associations for colorectal cancer, of which 50 had not been previously reported. The TWASs and MWASs revealed an additional 53 gene variants linked to the disease. The study was two times as large as previous GWAS of CRC and the mixed ethnicity of the groups—inlcuding both European and Asian ancestries—demonstrated that most of the loci are shared across the groups.
The findings also validated more commonly known risk factors for CRC, including insulin resistance, smoking, and obesity, which have been observed and reported in previous epidemiological studies.
Colorectal cancer is a leading cause of death around the globe. “Colorectal cancer is a serious disease, but it is preventable and can be successfully treated if detected early,” said William Grady, MD, director of the GI Cancer Prevention Program Clinic and a professor at Fred Hutch. “This study has the potential to pave the way for better screening and prevention, allowing us to improve our current ways of determining who is at higher risk.
”Germline genetic risks or gene mutations—those that you inherit from your biological parents—play a vital role in cancer risk and susceptibility. “Knowing these hereditary factors and which groups are at greatest risk from them can guide clinicians in recommending preventive measures and more frequent screenings which can lead to earlier diagnosis and treatment and better survival outcomes for patients,” pointed out co-first author Minta Thomas, PhD, a staff scientist at the Fred Hutch.
Based on their findings, the researchers and collaborators now plan to use the results to develop tests based on germline DNA that can categorize individuals at high genetic risk for colorectal cancer, and those who may have only a minimal likelihood of developing the disease.
A longer-term goal is to combine genetic risk data with other risk factors—environmental, dietary, and behavioral (such as smoking)—to create multifaceted polygenic risk scores (PRS) to more precisely determine person’s risk of developing CRC.
My mother died of colon cancer in 1990. State of the art was nowhere as detailed as it is today. In truth, my mother denied that she had a problem; she lied to me about doctor visits and, when there was no alternative, allowed physician-advised surgery. The surgeon came out to where we, the family, awaited and said that when he opened her up, he found such extensive carcinomas that he stitched her back up and sent her on her way! Of course, exposure to oxygen allowed the cancer to really take off. That is when I interceded and found a “competent” oncologist to help. He prescribed 5-fluorouracil, which indeed sent the cancer into remission. Mom was improving when she suffered a series of strokes, compounded by heart failure. This killed her. Yes, “Life finds a way,” but so does Death. About 20 years later, I was introduced to the “new” field of epigenetics. Now, I ask — and specifically relating to the comprehensive study at Fred Hutchinson — could DNA “tags” (methylations) be what is allowing colon cancer risk factors to be passed to subsequent generations, and not necessarily point mutations in the genome?