In a groundbreaking study published today in Nature Genetics, Stanford researchers identified nearly 400 key genetic switches that affect a person’s lifelong risk of cancer, thus providing relevant genetic DNA New insights into how mutation affects disease.
The research team led by Dr. Paul Khavari, PhD, chairman of Stanford Medical Dermatology, analyzed more than 4,000 DNA variants associated with cancer risk, and ultimately pointed out 380 that actively control gene expression. Their findings can revolutionize how doctors assess cancer risk and develop prevention strategies.
“We distilled large compendia of information from millions of people diagnosed with any of the 13 most common cancer types, which constitution over 90% of all human malignancy,” said Khavari, who is the Carl J. Herzog Professor in Dermatology in the School of Drug. “The massive funnel of data allows us to identify 380 variants that control the expression of one or more cancer-related genes. Some variants, if you unfortunately can inherit them from your parents, can increase the number of suffering from risk of cancer.”
Unlike previous studies that identified only more common DNA variants in cancer patients, the study shows which variants actually alter gene activity in ways that promote cancer development. The team analyzed these changes in relevant human cell types—for example, variants associated with lung cancer in lung cells—to understand their actual biological effects.
This comprehensive approach has led to the identification of approximately 1,100 target genes affected by these DNA switches. Some genes specifically target certain cancer types, while others appear to increase the risk of multiple cancers. The study reveals several common biological pathways affected by these changes, including how cells repair DNA damage, produce energy, and interact with the environment.
A surprising discovery is the important role of inflammation-related genes. “One pathway that really pops up includes many genes that are closely related to inflammation,” Havari explained. “Although there has been a link between inflammation and cancer, it is not clear what is driving the process – Cancer Cell or immune system. This finding suggests that communication may occur between cells and the immune system, driving chronic inflammation and increasing cancer risk.”
This study represents a significant advance in current genetic screening methods that focus primarily on a handful of well-known mutations, such as the BRCA genes associated with breast and ovarian cancer. The newly identified variant is a regulatory region that controls when and where other genes are expressed, rather than the gene itself.
Using gene editing techniques, the researchers demonstrated that about half of these variants were intended to support sustained cancer growth in laboratory conditions. This suggests that targeting these pathways may lead to new therapeutic strategies.
“Now we have the first generation of mapping of functional single nucleotide variants that determine a person’s lifespan cancer risk,” Khavari said. “We expect that this information will be incorporated into an increasing number of informational heredity,” Khavari said. In screening tests, these tests will be available over the next decade to help determine who is most at risk of many genetically complex diseases, including cancer. This general approach may help personalize common diseases. Risk assessments to guide interventions such as lifestyle changes, pharmacological preventive agents and diagnostic screenings.”
The study, led by former graduate student Laura Kellman, is part of a larger project funded by the National Institute of Human Genomes, which develops an atlas of regulatory variants in the disease. The program aims to identify variants associated with 42 common complex diseases, develop personalized risk scores and propose new treatments.
These findings may have far-reaching implications for cancer prevention and treatment. By understanding which genetic variants contribute significantly to cancer risk, physicians may be able to better identify patients who require more frequent screening or preventive interventions. In addition, identifying common biological pathways affected by these changes may lead to new therapeutic targets for cancer prevention or treatment.
The study was supported by the U.S. Office of Veterans Research and Development Affairs and the National Institutes of Health.
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