Key Takeaways
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A family tree is usually a record of names, dates and places. Sometimes it also holds a clue about health. This Lung Cancer Awareness Month, we are looking at how 23andMe scientists used genetic ancestry to follow a rare lung cancer risk variant back more than 200 years to the mountains of the American Southeast.
In September, we shared the results of a collaboration between the 23andMe Research Institute and Dana-Farber Cancer Institute that was published in Science. People who inherit a variant called T790M in the EGFR gene had 25 times higher odds of developing lung cancer. Among more than 10 million consented research participants in this study, 641 carried this genetic variant. While the variant is rare, we wanted to share more about where the variant came from and why that history could matter for lung cancer screening.
How Did Scientists Trace a Lung Cancer Variant to Southern Appalachia?
We combined birthplace data, shared DNA and genetic dating to show that most carriers of the EGFR T790M variant descend from settlers of Southern Appalachia who lived in the early 1800s.
The first clue was geography. Carriers disproportionately reported that they or their grandparents were born in the Southern U.S., particularly Tennessee, Alabama and Georgia.
Next, we looked at stretches of DNA that are identical by descent (IBD), meaning chunks of DNA that two people share because they inherited them from the same ancestor. We compared carriers with more than 3.4 million consented 23andMe research participants who reported where their grandparents were born. Shared DNA peaked in Southern Appalachia, with the strongest signal along the border between northern Alabama and southern Tennessee. We also saw that carriers were more likely to have connections to Genetic Groups representing colonial populations from Southern Appalachia.
Finally, we estimated when carriers’ most recent shared ancestor lived. Every time DNA passes from parent to child, it gets reshuffled, which breaks long shared segments into shorter pieces. That means the length of a DNA segment two people share says something about how many generations separate them from a common ancestor. We measured all the segments of DNA that EGFR T790M carriers share across their genomes and used a statistical model to estimate how many generations back they shared an ancestor. We estimated that carriers in the Southern Colonial Genetic Group share an ancestor who lived around 1799. Carriers with recent British and Irish ancestry were estimated to share an older ancestor, which suggests the EGFR T790M variant arose in Europe and crossed the Atlantic with settlers of British and Irish descent.
Together these results point to a founder event. A founder event happens when a small group splits off from a larger population and a once-rare variant becomes more common among the descendants of that smaller group. As settlers moved into isolated mountain communities in Appalachia around 1800, the EGFR T790M variant became more common there than anywhere else. Today, up to 1 in 2,000 people born in states in the Southeastern U.S. are carriers.
Who Carries the EGFR T790M Variant Today?
Most EGFR T790M carriers trace their ancestry to Southern Appalachia, but the variant has also spread into other communities over the past 200 years.
About 72% of carriers had recent ancestry from an American Southern Colonial group, and they shared a very large (23,700,000 base pairs long!) identical segment of DNA originating from the founder event. Others had African American ancestry, Indigenous American ancestry or Acadian and French Canadian ancestry. These other carriers were estimated to share more recent ancestors, from the early to mid-1900s, but in every case the section of DNA that contained the EGFR T790M variant traced back to European ancestry. Migration out of the Southeast after the Civil War likely carried the variant into these families. Though, even today, there are a small number of carriers still living in Europe.
This matters because ancestry is often more complex than a single label. Someone who identifies as Black or Native American could still carry a genetic variant that entered their family tree from a European ancestor generations ago.
Could Your Ancestry Help Guide Lung Cancer Screening?
Ancestry might one day help doctors identify people who may benefit from genetic testing for the EGFR T790M variant, but more research is needed before it shapes screening guidelines.
Today, U.S. lung cancer screening recommendations are based on age and smoking history. The American Cancer Society recommends a yearly low-dose CT scan for adults ages 50 to 80 who have a 20 pack-year smoking history.
That approach would miss many EGFR T790M carriers. In the study, about two-thirds of carriers reported never smoking. Further research — like that happening through the INHERIT study led by Dana-Farber or the Lung Cancer Genetics Study — could provide more insights into better lung cancer screening and prevention options for people with this or other genetic risk factors.
What You Can Do
These steps can help you understand and lower your lung cancer risk.
- Learn your family health history. Note any relatives diagnosed with lung cancer, especially those who never smoked or were diagnosed at a younger age.
- Talk with a doctor or genetic counselor if lung cancer runs in your family. They can help you decide whether genetic testing, lung cancer screening or other actions make sense for you.
- Test your home for radon, and reduce levels if they’re high. Radon is the second leading cause of lung cancer overall and the leading cause of lung cancer among people who have never smoked.
- As much as possible, avoid air pollution and workplace exposure to certain chemicals (such as asbestos) that can increase the risk for lung cancer.
- Avoid tobacco smoke, including secondhand smoke. Smoking remains the top risk factor for lung cancer.
If you have a history of smoking, you may be eligible for lung cancer screening that can find lung cancer early, when it’s most treatable. Talk to your healthcare professional about what screening might be right for you.
To dig deeper into the risk findings, read our first post on the EGFR T790M variant or explore the full study in Science.
