Stanford scientists have identified 380 key genetic variants that significantly influence cancer development, filtering through vast datasets to separate impactful mutations from irrelevant ones.
These variants regulate genes tied to DNA repair, energy production, and immune system interactions, shedding new light on inherited cancer risks. Surprisingly, inflammation-related genes also emerged as potential cancer drivers. This research marks a major step toward precise genetic screening and personalized prevention strategies.
Unraveling the Genetic Risk of Cancer
Thousands of tiny changes in the DNA sequence of the human genome have been linked to an increased risk of cancer. However, until now, it has been unclear which of these changes directly contribute to the uncontrolled cell growth that defines the disease and which are simply coincidences or minor players.
Stanford researchers conducted the first large-scale analysis of these inherited genetic changes, known as single nucleotide variants. Their study identified fewer than 400 variants that play a key role in triggering and sustaining cancer growth. These variants influence several critical biological pathways, including those that control DNA repair, energy production, and how cells interact with their microenvironment.
Common Biological Pathways and Cancer Growth
By highlighting these common genetic factors, the findings could open the door to new strategies for preventing or slowing cancer growth. The researchers also believe this knowledge could improve genetic screening, helping to better assess an individual’s lifetime risk of developing cancer.
“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 Paul Khavari, MD, PhD, chair of dermatology. “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.”
Khavari, who is the Carl J. Herzog Professor in Dermatology in the School of Medicine, is the senior author of the research, which was published today (February 17) in Nature Genetics. Former graduate student Laura Kellman, PhD, is the lead author of the study.
The Risks We Inherit
The study focused on DNA sequences inherited at conception, known as a person’s germline genome, rather than on mutations that can accumulate during a person’s lifetime as cells divide during development or to repair injury. Examples of well-known inherited cancer-associated mutations are the BRCA1 and BRCA2 genes that confer a significantly increased risk of breast and ovarian cancers. However, only a few of these high-profile mutations are currently used to predict cancer risk.
The variants Kellman and Khavari identified are not in so-called “coding” genes, which encode the instructions to make proteins that do much of the work of the body. Instead, they are in regulatory regions that control whether, when, and how much these genes are expressed. Often these regulatory regions influence the expression of nearby genes; sometimes they influence distant genes.
In 2020, Khavari launched a research project funded by the National Human Genome Research Institute to develop the Atlas of Regulatory Variants in Disease to pinpoint variants linked to the risk of developing 42 common complex diseases including cancers, develop individualized risk scores for each disease to aid in screening and prevention, and suggest new treatment strategies.
A New Approach to Understanding Cancer Risk
Previous studies, known as genome-wide association studies, identified variants found more often in people with specific kinds of cancers than in their cancer-free peers — a kind of guilt-by-association metric. But these studies, of which there have been many, fall short of proving that the variations change the activity of the regulatory region in ways that pump up or tamp down the expression of the genes they regulate; they also do not identify which genes are affected.
Kellman, Khavari, and their colleagues took a different approach. They amassed over 4,000 suspect variants identified by genome-wide association studies, or GWAS, in 13 types of cancer and tacked those regulatory regions — along with control sequences — to DNA sequences, each with a unique bar code. They then conducted what are known as massively parallel reporter assays to determine which variants changed the expression of the bar-tagged sequence in the relevant cell type, testing variants associated with lung cancer in human lung cells, for example.
Winnowing thousands of potential variants down to a few hundred functional regulatory regions allowed the researchers to combine information from pre-existing databases about DNA folding, tissue-specific gene expression profiles, and others to identify about 1,100 target genes likely to play a role in cancer development. Some are specific to a certain type of cancer while others appear to increase the risk of several cancers.
“A lot of these genes make sense in the context of what we know about cancer development,” Khavari said. “Some are involved in cell death pathways, and others affect how cells interact with the extracellular environment, for example. One of the most prominent pathways is involved in the function of cellular mitochondria — tiny cellular energy factories that support cell growth and division.”
The Immune System’s Role in Cancer Development
But the researchers also found things that surprised them.
“One pathway that really popped out includes a number of genes closely associated with inflammation,” Khavari said. “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 Future of Cancer Screening and Prevention
Finally, the researchers used gene editing techniques in laboratory-grown cancer cells to show that as many as half of the variants are required to support ongoing cancer growth. They expect the study’s findings will be a springboard for researchers around the world seeking to understand inherited cancer risk and develop new therapies.
“Now we have a first-generation cartographic map of functional single nucleotide variants that determine a person’s lifetime cancer risk,” Khavari said. “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.”
Reference: “Functional analysis of cancer-associated germline risk variants” by Laura N. Kellman, Poornima H. Neela, Suhas Srinivasan, Zurab Siprashvili, Ronald L. Shanderson, Audrey W. Hong, Deepti Rao, Douglas F. Porter, David L. Reynolds, Robin M. Meyers, Margaret G. Guo, Xue Yang, Yang Zhao, Glenn G. Wozniak, Laura K. H. Donohue, Rajani Shenoy, Lisa A. Ko, Duy T. Nguyen, Smarajit Mondal, Omar S. Garcia, Lara E. Elcavage, Ibtihal Elfaki, Nathan S. Abell, Shiying Tao, Christopher M. Lopez, Stephen B. Montgomery and Paul A. Khavari, 17 February 2025, Nature Genetics.
DOI: 10.1038/s41588-024-02070-5
The study was funded by the U.S. Veterans Affairs Office of Research and Development and the National Institutes of Health (grants AR076965, AR43799, CA142635 and U24HG010856).
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