Pancreatic ductal adenocarcinoma (PDAC) is a tough disease to diagnose and treat. Scientists have also had a hard time figuring out what causes this aggressive cancer.
They do know that roughly 95% of PDAC tumors have a change, or mutation, in a gene called KRAS. KRAS belongs to a family of genes called RAS, which normally controls how cells grow and divide in your body. If KRAS is changed, it can't turn off the growth of cells.
"When pancreatic cancer develops, it acquires a genetic mutation in the gene that codes for KRAS, leading it to favor the 'on' state, which leads to cancer growth and spread," explains Brandon Huffman, MD, assistant professor of medicine at Harvard Medical School and medical oncologist at Dana-Farber Cancer Institute in Boston.
These mutations are not inherited. Instead, they develop over time. Researchers are still working to fully understand what causes them.
Why Do RAS Mutations Occur?
Huffman says, "The mechanisms are unclear for why KRAS mutations develop." Still, scientists have some clues about the potential causes.
Spontaneous mutation
KRAS mutations aren't something you're born with. Rather, they occur during your lifetime.
Many KRAS mutations happen spontaneously as cells divide. Each time a cell splits, small errors can occur. Over time, these mistakes can accumulate, especially in the pancreas, which is exposed to metabolic and inflammatory stress. This is one reason PDAC is more common with increasing age. The longer you live, the more time there is for mutations to form.
Environmental and lifestyle factors
Most PDAC mutations are due to random DNA errors and can't be prevented. But others may be caused by environmental or lifestyle factors.
Certain exposures or conditions that may increase the likelihood of RAS mutations by damaging DNA or promoting chronic inflammation include:
- Smoking. Tobacco smoke contains dangerous compounds that directly damage DNA. It's one of the strongest known risk factors for PDAC. Studies show smokers are significantly more likely to develop KRAS mutations.
- Dietary factors. Diets high in processed meats and low in fruits and vegetables may increase oxidative stress and inflammation, which can contribute to DNA damage.
- Chemicals. Occupational exposure to certain industrial chemicals (such as solvents, petroleum products, and possibly asbestos) has been linked to higher pancreatic cancer risk.
- Chronic inflammation. Conditions like chronic pancreatitis can create an environment where DNA damage, and therefore KRAS mutations, are more likely to occur.
- Alcohol. Heavy alcohol use of three or more drinks a day has been linked to an increased risk of PDAC.
Obesity and metabolic health
Obesity is linked to a higher likelihood of PDAC. The theory is that being overweight may create conditions that support the growth of KRAS-mutated cells. Excess body weight can promote inflammation, insulin resistance, and growth signaling pathways that make it easier for cells with altered DNA to survive and expand. At the same time, KRAS mutations can alter metabolism in ways that further promote tumor growth.
Can You Reduce Your Risk of an RAS Mutation?
Not all KRAS mutations can be prevented, especially those caused by aging or random genetic errors. However, you can reduce certain risk factors and lower your likelihood of mutations if you:
- Avoid tobacco use
- Maintain a healthy weight
- Eat a nutrient-rich diet
- Limit exposure to harmful chemicals
- Manage chronic inflammatory conditions
If you have an RAS mutation, these healthy habits can help you tolerate treatment better. Additionally, they can support your general health and quality of life.
How Is RAS Testing Done and What Does It Suggest About Causes?
Testing for a KRAS gene mutation, which is sometimes called biomarker testing, helps doctors better understand your cancer. Based on the results, they can offer you treatment options that are more likely to be effective.
There are two ways to test for an RAS mutation:
- Tissue biopsygenetic testing. A sample of tissue from your tumor is tested in a lab.
- Liquid biopsy. A blood draw is done. Doctors look for pieces of tumor DNA in your blood.
The results of these biomarker tests can reveal:
- If you have a KRAS mutation
- The specific KRAS mutation you have (there are several)
- Other mutations you have
While testing doesn't determine the exact cause of your mutation, patterns may reflect underlying processes, such as DNA damage from smoking or aging.
Why Testing and Understanding Causes Both Matter
Even though testing is essential for treatment planning, understanding what may have caused a KRAS mutation can also be meaningful.
Helps doctors understand your cancer
Biomarker testing can provide a clearer picture of your cancer. And recognizing contributing factors, such as smoking or metabolic problems, may help identify supportive care strategies alongside treatment.
Understanding the cause of your gene mutation could also help doctors detect cancer earlier and recommend ways to reduce your risk.
Guides treatment decisions
A key benefit of testing is that the results can help your doctor make treatment decisions.
"Some KRAS inhibitors are targeted at certain types of KRAS mutations," explains Huffman. "Those specific KRAS inhibitors do not work on all KRAS mutations, so identifying which KRAS mutation is in the tumor will be critical."
Knowing the cause of the mutation is also an important piece of the puzzle. This information could allow doctors to come up with ways to prevent the disease and stop the gene mistake from ever happening. For instance, they can recommend a treatment, like weight loss surgery, for people with obesity.
Supports research into better treatments
Understanding why KRAS mutations happen in the first place can help scientists design new treatments. And tumor testing can help them create personalized medicines that target specific gene mistakes.
Scientists have developed new treatments to target tumors with this gene defect.
"The long-standing characterization of mutant KRAS as 'undruggable' has been fundamentally challenged over the past several years with multiple promising strategies now in active clinical and preclinical development," says Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center.
What About Genetic Testing?
Genetic testing can help you find out if your family carries an inherited gene mutation that's passed down from parent to child. While KRAS gene mutations happen over time and don't run in families, other gene mutations do. A genetic test is helpful to see if you have any inherited gene mutations, which could affect your treatment options.
Takeaways
Doctors are learning more about what causes gene mistakes like the KRAS mutation. Most of these mutations develop due to spontaneous DNA errors, environmental exposures, and lifestyle-related factors such as smoking and obesity. While they can't be reversed, understanding their causes may help reduce risk and support overall health.
Show Sources
Photo Credit: iStock/Getty Images
SOURCES:
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