In a groundbreaking study published today in Nature Genetics, Stanford researchers have identified nearly 400 key genetic switches that influence a person’s lifetime risk of developing cancer, providing new insights into how inherited DNA variations contribute to the disease.
The research team, led by Dr. Paul Khavari, chair of dermatology at Stanford Medicine, analyzed over 4,000 DNA variations linked to cancer risk, ultimately pinpointing 380 that actively control gene expression. Their findings could 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 constitute over 90% of all human malignancies,” said Khavari, who is the Carl J. Herzog Professor in Dermatology in the School of Medicine. “This enormous funnel of data allowed us to identify 380 variants that control the expression of one or more cancer-associated genes. Certain variants, if you are unlucky enough to inherit them from your parents, can increase your risk of developing many types of cancer.”
Unlike previous studies that merely identified DNA variations more common in cancer patients, this research demonstrates which variants actually alter gene activity in ways that could promote cancer development. The team analyzed these variations in relevant human cell types – testing lung cancer-associated variants in lung cells, for example – to understand their real biological impact.
This comprehensive approach led to the identification of approximately 1,100 target genes influenced by these DNA switches. Some genes were specific to certain cancer types, while others appeared to increase the risk of multiple cancers. The research revealed several common biological pathways affected by these variations, including how cells repair DNA damage, produce energy, and interact with their environment.
One surprising discovery was the prominent role of inflammation-related genes. “One pathway that really popped out includes a number of genes closely associated with inflammation,” Khavari explained. “While a connection has been established between inflammation and cancer, it’s not been clear what was driving this process – the cancer cells or the immune system. This finding suggests there may be cross talk between cells and the immune system that drives chronic inflammation and increases cancer risk.”
The study represents a significant advance over current genetic screening methods, which primarily focus on a handful of well-known mutations like the BRCA genes associated with breast and ovarian cancers. The newly identified variants are in regulatory regions of DNA that control when and how much other genes are expressed, rather than in genes themselves.
Using gene editing techniques, the researchers demonstrated that about half of these variants are required to support ongoing cancer growth in laboratory conditions. This suggests that targeting these pathways could lead to new therapeutic strategies.
“Now we have a first-generation cartographic map of functional single nucleotide variants that determine a person’s lifetime cancer risk,” said Khavari. “We expect that this information will be incorporated into increasingly informative genetic screening tests that will become available over the next decade to help determine who is most at risk for many types of genetically complex diseases, including cancer. This general approach may help provide an individualized risk assessment for common diseases to guide interventions, such as lifestyle changes, pharmacologic preventatives and diagnostic screening.”
The research, led by former graduate student Laura Kellman, is part of a larger project funded by the National Human Genome Research Institute to develop the Atlas of Regulatory Variants in Disease. This initiative aims to identify variants linked to 42 common complex diseases, develop personalized risk scores, and suggest new treatment approaches.
The findings could have far-reaching implications for cancer prevention and treatment. By understanding which genetic variations contribute significantly to cancer risk, doctors may be able to better identify patients who need more frequent screening or preventive interventions. Additionally, the identification of common biological pathways affected by these variations could lead to new therapeutic targets for cancer prevention or treatment.
The study was supported by funding from the U.S. Veterans Affairs Office of Research and Development and the National Institutes of Health.
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