Landmark Study Reveals a Powerful Inherited Lung Cancer Risk Variant and its Colonial American Roots

By Steven Micheletti, Ph.D. and Stella Aslibekyan, Ph.D.

Key Takeaways The EGFR T790M variant confers a significantly elevated risk for lung cancer, increasing the odds by over 25 times for carriers. This variant, while still rare, was found at a frequency approximately ten times higher than what had been previously reported. The higher frequency of the variant in people of British and Irish descent in the Southeastern United States was traced to early European settlers in this region. This highlights the important reality that factors beyond exposure to tobacco smoke may increase someone’s risk for lung cancer.

Anyone with lungs can get lung cancer. And while many people think exposure to tobacco smoke is the only risk factor, tens of thousands of Americans without this risk factor are diagnosed with lung cancer every year, showing that smoking is by no means the whole story of lung cancer risk. For many people with lung cancer the question of why has had no good answer. For some, a new study is starting to change that.

A collaboration between the 23andMe Research Institute and Dana-Farber Cancer Institute, one of the world’s leading centers of cancer research and treatment, has shown that a specific, rare genetic variant in the EGFR gene, the T790M variant, is the largest known single genetic risk factor for lung cancer. This research, published today in Science, is a crucial step for clinical genetics, potentially transforming lung cancer screening efforts. It is also a fascinating detective story, tracing the variant’s origins back to the colonial history of the American Southeast.

Unmasking of a Powerful Lung Cancer Risk Variant

Not all EGFR T790M changes are the same. This variant is well-known as a mutation that occurs within a tumor and helps lung cancers resist treatments. This study looked at something different: people who inherit this genetic variant and have it in each of their cells since birth. 

This inherited version of the EGFR T790M variant has been reported before in small studies of families with multiple cases of lung cancer. However, the inherited form of this genetic variant is so rare that researchers have struggled to establish precise estimates for how it impacts lung cancer risk or even understand how common this variant really is. The scale of research participation at the 23andMe Research Institute changed this entirely.

More Common and More Impactful Than Expected

Out of over 10 million consented research participants, 641 carried the EGFR T790M variant. While still rare, this is approximately ten times higher than that reported in public databases like gnomAD. 

Overall, people with this variant had 25x higher odds of developing lung cancer. To put this into perspective, this relative risk is equal to or higher than that of other well-established inherited cancer risk genetic variants, such as those in the BRCA1 and BRCA2 genes for breast and ovarian cancer. And while exposure to tobacco smoke is still the number one risk factor for lung cancer, in the study this variant put people at even higher risk than having a history of smoking.

The study also highlighted a rare phenomenon: the risk associated with the EGFR T790M variant is specific to lung cancer alone. Often genetic variants that dramatically increase the risk of one cancer also increase the risk of other cancers, but for people with the EGFR T790M variant there were no significant associations with other frequent cancers, including breast, prostate or colorectal cancer. This finding could help people with this variant know the specific, targeted screening they may need.

A Genetic Ancestry Detective Story

One of the greatest strengths of the 23andMe Research Institute is the ability to combine different scientific disciplines to deeply understand genetics, health and history. In this case, 23andMe scientists were able to analyze geographic data and genetic relatedness among those with the EGFR T790M variant to uncover a distinct historical pattern and trace the origin and spread of this rare variant.

People who have the EGFR T790M variant (or “carriers”) disproportionately traced their ancestry to the Southern U.S., particularly Tennessee, Alabama, and Georgia. Using sophisticated genetic dating methods, 23andMe researchers estimated that carriers of the EGFR T790M variant in the Southern Appalachian region shared an ancestor who lived in the early 19th century. Around this time was when early European settlers expanded into the Southern Appalachian region forming smaller tight-knit communities prior to the Civil War.

The data supports that the EGFR T790M variant, likely originating in Europe, was carried by early settlers of British and Irish descent to the Southeastern United States. During the late 18th century, regional expansion and demographic isolation led to a founder effect, where a small group is genetically separated from a larger population. This genetic bottleneck significantly increased how common the EGFR T790M variant is within this specific subpopulation, with researchers finding that people with ancestry from the Southern United States are six times more likely to carry the variant than those from other regions. This is one of the most recent founder events of a medically important variant. This may enable doctors and researchers to identify potential carriers based on where their ancestors were from.

The Power of the 23andMe Research Institute

This research stands out precisely because it would have been extremely difficult using traditional methods. The study highlights the strength of the 23andMe Research Institute, which combines two crucial elements:

1. Large-Scale Data: The sheer size of the research community (over 11 million consented research participants) provided the necessary power to detect the 641 EGFR T790M carriers and characterize the risk from this rare genetic variant. For comparison, the UK Biobank and All of Us databases, while large, contained only 2 and 19 carriers, respectively, making a robust risk assessment impossible with those databases.
2. Wide Variety of Genetics Expertise: This collaboration of researchers, spanning epidemiology, oncology, statistical genetics, and population genetics, was able to go beyond a simple association. They used self-reported data, deep ancestry analysis, and complex genetic dating to not only better understand the magnitude of the lung cancer association but also to contextualize the variant in history.

By bringing together a large number of consented research participants and diverse expertise, 23andMe has been able to help shine a light on the most significant single genetic risk factor for lung cancer to date, and link it directly to an important moment in American history. This discovery underscores the power of large-scale genetic studies to transform our understanding of rare, high-risk genetic variants and potentially reshape clinical screening and public health efforts.

Data analyzed in this study includes participants in the Lung Cancer Genetics Study, an initiative funded by the Susan Wojcicki Foundation and powered by 23andMe in collaboration with 22 lung cancer advocacy organizations. By uniting the stakeholders that support the patients and families living with this critically underfunded disease, the Lung Cancer Genetics Study hopes to help contribute to more discoveries like this in the future.

Additional data came from participants in the INHERIT (Investigating Hereditary Risk in Thoracic Cancers) Study, led by the Dana-Farber Cancer Institute in partnership with GO2 for Lung Cancer (GO2) and the Addario Lung Cancer Medical Institute (ALCMI), which aims to to further understand the genetic risk and predispositions for developing lung cancer.

Learn more about the Lung Cancer Genetics Study and INHERIT.