Researchers identify a rare inherited gene mutation that substantially raises a person's risk of developing lung cancer

Today, eligibility for lung cancer screening is based on a narrow definition of risk — whether someone is at least age 50 and has smoked the equivalent of a pack of cigarettes per day for twenty years — leaving out younger people and people with different smoking histories or other risk factors. As a result, about half of all people diagnosed with lung cancer would be ineligible for screening, and until now, genetics has rarely factored into how we think about who is at risk. Expanding that picture is one of our top priorities.

A new study published in Science from researchers at the Dana-Farber Cancer Institute and the 23andMe Research Institute sheds promising new light. Researchers found that a rare inherited change in a gene called EGFR, specifically a variant known as T790M, is associated with 25x higher risk of lung cancer. Carriers of the EGFR T790M variant disproportionately traced their ancestry to the Southeastern U.S., particularly Tennessee, Alabama, and Georgia. Data analyzed in the study includes participants in the Lung Cancer Genetics Study, which is funded by the Susan Wojcicki Foundation and powered by the 23andMe Research Institute in collaboration with 22 lung cancer advocacy organizations.

Why this EGFR mutation is different

Not all EGFR T790M mutations are the same. There are two distinct types, and they have different implications for patients. 

The first type of EGFR T790M mutation develops only within a tumor itself. It can arise over time as cancer cells develop resistance to certain targeted lung cancer drugs called EGFR inhibitors. This type of mutation is found only in tumor tissue, through biomarker testing of a tumor sample. It is not inherited, so it cannot be passed from parent to child.

The second type of EGFR T790M mutation, the one researched in this study, is inherited. This means a person was born with the mutation, and it is present in every cell in their body. It's detected through genetic testing of blood or saliva. This inherited EGFR T790M mutation can be passed down from parent to child and can run in families. 

Prior to this study, researchers had identified the inherited mutation in small studies of families with multiple cases of lung cancer. However, because it is so rare, they weren’t able to develop precise estimates of how much it impacts risk or even how common the mutation is. The study team set out to change that.

What the researchers found

The team analyzed genetic data from more than 3.3 million people. Those with the mutation (also known as carriers) had 25x higher odds of developing lung cancer compared with non-carriers. To put this number 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 cancer and ovarian cancer. The mutation was not linked to any of the 17 other cancers researchers studied, suggesting its effect is largely specific to the lungs.

By tracing the mutation's history, researchers also found it became unusually common within a specific group: families connected to the Southern Appalachian region of the United States. They link this finding back to what scientists call a founder event, when a small group of people (or founders) is isolated from the larger population, allowing an otherwise rare genetic variant to become more common in the small group. In this case, the founder event happened roughly 200 years ago. Nationally, about 1 in 15,000 people carry the mutation. The researchers found that people with ancestry from the Southern United States are six times more likely to carry the variant than those from other regions.

What comes next

Finding a signal this rare and this clear was made possible because diverse organizations care about expanding our understanding of risk, not settling for traditionally held narratives about who gets lung cancer. What comes next is more research: replicating these findings in more diverse populations and working out how inherited genetic risk should factor into screening decisions in practice. 

Redefining who is considered at risk, and expanding screening eligibility beyond smoking history alone, is central to our work. These are exactly the kinds of goals the Lung Cancer Genetics Study was built to support, and it's why we continue to invest in expanding who is included in it. You can learn more about the Lung Cancer Genetics Study, our collaborators, and eligibility criteria at the study website.

Read the full EGFR study in Science.

Frequently Asked Questions & Resources for Patients and Families

I’m concerned that I or my family might have the EGFR T790M inherited mutation. What should I do next?

If you have questions about your personal or family cancer risk, we encourage you to speak with a healthcare professional. The researchers involved in this study recommend that people with multiple lung nodules, multifocal lung cancers, several family members who have had lung cancer, or ancestral roots in affected areas of the Southeastern United States consult a genetic counselor. A counselor can help determine whether genetic testing and regular lung cancer screening may be appropriate. Please see the final FAQ on this page for resources related to genetic counseling.

A 25-fold increase in lung cancer risk sounds very large. Does that mean a carrier of the EGFR T790M mutation will get lung cancer?

No. The statistic does not refer to an individual person’s odds of getting lung cancer. Rather, it means that the group of people in this study with the mutation had 25x higher odds of lung cancer compared to a group of people without the mutation. Understanding why some carriers develop the disease and others never do is one of the next questions the researchers want to answer.

I live in Southern Appalachia or the Southeastern United States. Should I be concerned?

This mutation is more common in the Southeastern United States because of population history, not anything about the region itself. The mutation is rare — about 1 in 2,000 people are carriers in places where it’s most common. Family roots in Southern Appalachia are one reason among several that someone might want to speak with a genetic counselor about this mutation. Please see the final FAQ on this page for resources related to genetic counseling.

Does this finding apply to people of British or Irish descent who do not have family ties to the Southeastern United States? Does it apply to people who are not of European descent?

The researchers estimated that carriers of the EGFR T790M variant in the Southern Appalachian region shared an ancestor of European descent that likely lived in the region in the early 19th century. The carriers of the mutation identified in this study overwhelmingly descended from this ancestor. 

The researchers inferred that only about 6% of the carriers included in this study had direct ancestry in the United Kingdom (meaning that they or their parents were born in the UK). The researchers did not report how common this variant might be in the UK as a whole. For reference, in the UK Biobank, a large biomedical research database containing detailed health, genetic, and lifestyle information from volunteer participants in the UK, the frequency of the mutation is only 2 out of ~500,000 people.

Because the EGFR T790M carriers identified in this study overwhelmingly came from one European founder lineage, the researchers’ estimates of how common the variant is shouldn’t be generalized to other groups. Future studies will include more diverse populations and look at other inherited EGFR mutations that may increase lung cancer risk.

If you have questions about your personal or family cancer risk, we encourage you to speak with a healthcare professional.

I have already been diagnosed with lung cancer. What do the results of this study mean for my care?

Not all EGFR T790M mutations are the same. There are two distinct types, and they affect your care differently.

The first type of EGFR T790M mutation develops only within the tumor itself. It can arise over time as cancer cells develop resistance to certain targeted lung cancer drugs called EGFR inhibitors. This type of mutation is found only in tumor tissue, through biomarker testing of a tumor sample. It is not inherited, so it cannot be passed from parent to child.

The second type of EGFR T790M mutation, the one researched in this study, is inherited. This means a person was born with the mutation, and it is present in every cell in their body. It's detected through genetic testing of blood or saliva. This inherited EGFR T790M mutation can be passed down from parent to child and can run in families. This mutation increases the odds someone will develop lung cancer.

If you've been diagnosed with lung cancer and also carry the inherited form of EGFR T790M, it's important information for your care team. For example, your care team can help gather information for you to share with family members who may also have the mutation. In addition, the inherited mutation could impact your eligibility for some clinical trials or, in rare cases, which treatments may work best. If you have questions about what this mutation means for your treatment or your family's risk, we encourage you to speak with your care team. 

Questions to ask your care team:

• I have been diagnosed with lung cancer and am worried about my family’s risk. Should I consult with a genetic counselor?
• Can you provide me with a referral to a genetic counselor?
• Should my family members also consider meeting with a genetic counselor?
• If I have the inherited EGFR T790M mutation, how does that impact my care plan? 

Please see the final FAQ on this page for resources related to genetic counseling.

I have EGFR-positive lung cancer. Should I be concerned that I might have the inherited EGFR T790M mutation?

Researchers know that the inherited EGFR T790M mutation increases the odds of developing lung cancer. However, because the mutation is so rare, the tumors that develop in people with the inherited mutation have not been well studied. This means we do not yet know for certain what other biomarkers these tumors have. 

If you find the EGFR T790M mutation on your biomarker testing report and have questions about it, we encourage you to speak with your care team. If you do not have the mutation on your biomarker testing report and are concerned whether you might have the inherited version, we also encourage you to speak with your care team. 

Questions to ask your care team:

• Have I received genetic testing for the inherited (germline) EGFR T790M mutation?
• Is genetic testing appropriate for me? Should I consult with a genetic counselor?

The researchers involved in this study recommend that people with multiple lung nodules, multifocal lung cancers, several family members who have had lung cancer, or ancestral roots in affected areas of the Southeastern United States consult a genetic counselor. A counselor can help determine whether genetic testing may be appropriate. Please see the final FAQ on this page for resources related to genetic counseling.

If you have questions about what this mutation means for your treatment or your family's risk, we encourage you to speak with your care team. 

I have lung cancer, but my tumor biomarker testing found a biomarker other than EGFR or no biomarker at all. Does this study apply to me?

Researchers know that the inherited EGFR T790M mutation increases the odds of developing lung cancer. However, because the mutation is so rare, the tumors that develop in people with the mutation have not been well studied. This means we do not yet know for certain what other biomarkers these tumors have. However, based on what researchers know today, it is unlikely for someone to carry the inherited EGFR T790M mutation and to develop lung cancer that is driven by another oncogene (like KRAS, ALK, ROS1, RET, NTRK, BRAF, MET, or ERBB2/HER2). This is a rapidly evolving area of study. 

If you have questions about whether you might have the inherited EGFR T790M mutation, we encourage you to speak with your care team. 

Questions to ask your care team:

• Have I received genetic testing for the inherited (germline) EGFR T790M mutation?
• Is genetic testing appropriate for me? Should I consult with a genetic counselor?

The researchers involved in this study recommend that people with multiple lung nodules, multifocal lung cancers, several family members who have had lung cancer, or ancestral roots in affected areas of the Southeastern United States consult a genetic counselor. A counselor can help determine whether genetic testing may be appropriate. Please see the final FAQ on this page for resources related to genetic counseling.

How can I find out whether I carry the EGFR T790M mutation?

At this time, 23andMe does not have a report featuring the EGFR T790M variant. However, they are planning to make a report available in a future release because they think this is information that people should have and be able to bring to their doctor. We don’t yet have a timeline for when the report will be available.

EGFR T790M can be detected through genetic testing ordered by a healthcare provider. A genetic counselor is a healthcare professional with specialized training in medical genetics and counseling who helps people understand how genetic information impacts them and their families. A genetic counselor can help determine whether genetic testing may be appropriate for you. Please see the final FAQ on this page for resources related to genetic counseling.

I received genetic testing, and I have the inherited EGFR T790M variant. Should I get screened for lung cancer? Should my family members get genetic testing or lung cancer screening?

We encourage you to speak with a healthcare professional. A genetic counselor can help determine whether genetic testing and/or regular lung cancer screening may be appropriate. Please see the final FAQ on this page for resources related to genetic counseling.

Are there other inherited mutations linked to lung cancer?

Yes. EGFR T790M is the best-studied inherited change linked to lung cancer, but it’s not the only one. Researchers have found a small number of other genes that can run in families and increase the risk of lung cancer. Researchers are still learning how common each of these is and how much they impact a person’s risk of lung cancer. You can learn more about other inherited genes that increase lung cancer risk from the American Cancer Society. 

What is a genetic counselor? How can I speak with a genetic counselor about my risk for lung cancer?

A genetic counselor is a healthcare professional with specialized training in medical genetics and counseling who helps people understand how genetic information impacts them and their families. A genetic counselor can help determine whether genetic testing may be appropriate for you.

Learn about how to see a genetic counselor, and learn how to prepare for an appointment with a genetic counselor.

Note on evolving research

We still have much to learn about lung cancer risk. As research evolves, scientists and healthcare providers will continue to gain insight into how inherited EGFR T790M and other genetic and non-genetic factors impact lung cancer risk, diagnosis, and treatment. 

Disclaimer

This content on this blog is for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.