Researchers have found a significantly increased risk of lung cancer in individuals with an EGFR T790M germline variant, about 25 times higher than in noncarriers, according to study findings published in Science.
“Today, lung cancer screening is driven almost entirely by smoking history,” said co-study lead Jaclyn LoPiccolo, MD, PhD, attending physician and lung cancer researcher at Dana-Farber Cancer Institute. “Our findings raise the possibility that, in the future, screening could also be dictated by inherited genetic risk. If further studies confirm the benefit, people with EGFR T790M could be identified through genetic testing and offered personalized [computed tomography] screening to identify lung cancers when they are at their most curable stage.”
Background and Study Methods
The genetic basis of lung cancer in patients who have not smoked is poorly understood. Few risk-associated germline variants have previously been identified. The EGFR T790M germline variant has been associated with lung tumorigenesis related to a somatic activating EGFR mutation. Researchers sought to understand more about its frequency and risk.
The investigators conducted a case-control study of more than 3.3 million individuals with genotyped research through the direct-to-consumer genetic testing company 23andMe. They quantified the magnitude and specificity of related lung cancer risk in individuals with the EGFR T790M germline variant, assessed the relation of risk to smoking and polygenic susceptibility, evaluated its frequency and geographic distribution by global ancestries, and traced the origins of the variant.
Key Findings
The EGFR T790M germline variant was found in 1 out of 15,850 individuals and was significantly associated with an increased risk of lung cancer (odds ratio = 25.18; P = 1.9 x 10-24) vs noncarriers.
“For years we've known that some families inherit a markedly increased risk of lung cancer, but because this variant is so rare, we've never been able to accurately measure that risk,” said co-senior author Pasi A. Jänne, MD, PhD, Senior Vice President for Translational Research and a lung cancer specialist at Dana-Farber. “By studying more than 3 million people, we were able to demonstrate just how strongly this inherited mutation is associated with lung cancer.”
“One of the remarkable findings here is just how strong an effect a single mutation can have,” added co-senior author Alexander Gusev, PhD, a quantitative geneticist at Dana-Farber. “To my knowledge it's one of the strongest cancer risk increasing mutations that has ever been found.”
No significant associations were found with tested non–lung cancer types or noncancerous pulmonary conditions.
They tested associations in three independent polygenic risk score models and found no significant interactions between EGFR T790M and genome-wide lung cancer susceptibility. The researchers suggested that this indicated that the association was largely independent of polygenic background.
The effects of the variant was higher in individuals who had not smoked vs those who had.
In analysis of global ancestry, the researchers found that EGFR T790M came to the United States around 1803 with westward expansion, and that the variant is significantly enriched in U.S. vs British- and Irish-descendant populations, and especially among people of Southern Colonial ancestry. EGFR T790M variants did not seem to begin spreading to non-European populations until the early 1900s.
Further analysis found a recent founder effect in the Southern Appalachian region about 200 to 225 years ago, and the carrier frequency of this region is 1 in 2,078.
“We found that the vast majority of carriers inherited the mutation from the same ancestral lineage,” Dr. LoPiccolo said. “We could trace that lineage to British and Irish settlers in the United States and show that the mutation became enriched after a founder event and genetic bottleneck in Southern Appalachia about 200 years ago. It's a fascinating example of how human migration and genealogy can shape disease risk, generations later.”
DISCLOSURES: Funding for this study was provided by the LUNGevity Foundation; the Elaine & Gerald Schuster Fund for Lung Cancer Research; the National Institutes of Health; the American Cancer Society; the Chen-Huang Center for EGFR-Mutant Lung Cancers; GO2 for Lung Cancer (INHERIT Study); the Addario Family; Sam and Janet Bain; the Burns Family; the Jain and Patkar Family; David Lefkowitz and Julie Persily; the Smita and Pankaj Patel Family; SITA Foundation; The Van Auken Private Foundation; the Ray B. Marglous Family Foundation in memory of Lindsey Rae Marglous; the Michele Simeone Abrecht Memorial Fund, established by Charlotte and Clifford Abrecht; the Cammarata Family Foundation Research Fund; the Zhen-Quan Xu and Lin Yuan Fund for Lung Cancer Research; and the Gohl Family Lung Cancer Research Fund. For full disclosures of the study authors, visit science.org.
