Cancer is challenging to treat, yet identifying individuals with greater risk of developing disease can assist with early detection and increased treatment efficacy. There are several types of risk factors associated with cancer development including genetics, the environment, and behavioral traits like smoking tobacco. Since colorectal cancer (CRC) is a major cause of cancer-related deaths in the United States, researchers at the University of Washington and the Fred Hutchinson Cancer Center developed a genome-wide score to predict CRC risk. In order to identify prevention and treatment methods, the researchers wanted to find risk factors that may share underlying genetics with CRC. Their study published in Human Genomics describes a method using the genetic-based risk score and patient health record data to uncover associations between CRC risk and other medical record diagnoses (e.g. diabetes, alcohol use disorder, etc.).
Monogenic risk—or the risk associated with mutations in a single gene—accounts for about 20% of heredity-associated CRC. The remaining genetic-linked cases can arise from mutations across multiple loci in the genome—single nucleotide polymorphisms (SNPs)—that when found together (i.e. polygenic), increase the risk of CRC development. Using a person’s genotype data, a polygenic risk score (PRS) for CRC can be calculated. To uncover other medical record diagnoses with related genetic signatures, the researchers used an approach called phenome-wide association study (PheWAS). The strengths of this approach are that associations are genetically based, and risk of CRC can be correlated with patient specific diagnoses using accessible data in the patient’s medical records. Lead scientist, Dr. Elisabeth A. Rosenthal, shared their findings from this project, “We used a genetic score to estimate a person’s risk for CRC and found that this score is connected to genes underlying breast and prostate cancer, as well as genes underlying lifestyle factors like smoking, drinking alcohol, and being overweight. These findings match results from other types of studies and could help expand the role of genetic testing for CRC and guide new ways to prevent or treat CRC in more people.”
While understanding disease risk can be influenced by many factors, it is important to understand how genetics and environmental factors impact CRC risk. “In the future, we may be able to detangle the genetic risk from the environmental risk associated with modifiable behavioral traits,” shared Dr. Rosenthal. This approach of using PRS and diagnoses available in the patient’s health record is one step in that direction. Overall, the goal is to ensure that patient risk of CRC is assessed using all the available information to support early detection and if needed, treatment of disease.
The spotlighted research was funded by the National Human Genome Research Institute.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. William Grady, Li Hsu, and Ulrike Peters contributed to this work.
Rosenthal EA, Wei WQ, Luo Y, Namjou-Khales B, Schaid DJ, Esplin ED, Lape M, Kottyan L, Pacheco JA, Weng C, Gordon AS, Kullo IJ, Crosslin DR, Grady WM, Hsu L, Peters U, Jarvik GP. 2025. Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer. Hum Genomics. 19(1):77.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.
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