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Harvard Medical School team links 200-year-old founder effect to sharply higher lung cancer risk among non-smokers in southern Appalachia
This week’s cover of the international journal 'Science' features an illustration combining a human lung with a map of the United States. It indirectly depicts research findings that a gene mutation increasing lung cancer risk is concentrated in the southeastern region of the US. This work identifies a genetic legacy that can be traced back several centuries.
An international research team including Harvard Medical School in the United States analyzed genetic and health data from more than 3.3 million people and confirmed that a germline 'EGFR T790M' gene mutation is strongly associated with lung cancer risk. The results were published in Science on the 17th (local time).
The team analyzed 3,372,531 participants from the US genetic testing company '23andMe' and found that the T790M mutation occurs in about 1 out of every 15,850 people.
Carriers of the mutation had about a 25-fold higher likelihood of developing lung cancer than non-carriers, and no significant associations were observed with 17 other cancer types examined or with non-malignant lung diseases. The mutation was therefore identified as a lung-cancer-specific genetic risk factor. The effect of the genetic mutation was greater in people who had never smoked than in those with a history of smoking.
No interaction was observed with various polygenic risk score models, indicating that the impact of T790M is largely independent of general genetic susceptibility to lung cancer. The researchers explained that this mutation may contribute to lung tumor formation together with activating EGFR somatic mutations.
By tracing ancestry and geographic data, the team found that in the US the T790M mutation is more common—about 1 in 8,920 people—than in populations of British or Irish descent, and estimated that it expanded markedly through a 'founder effect' that arose about 200–225 years ago in the southern Appalachian region. A founder effect refers to a phenomenon in which a small group of people settling in a new region leaves certain mutations they carry at high frequency in their descendants by chance.
In southern Appalachia, the carrier frequency rose to about 1 in 2,078 people, and evidence showed that after population movements following the Civil War, the mutation spread into groups with African and Native American ancestry.
The researchers suggested that considering T790M testing in people with a family history of lung cancer, those with multiple lung cancers or lung nodules, and individuals with southeastern US ancestry could help identify high-risk groups.
These findings demonstrate a strong statistical association between the genetic mutation and the development of lung cancer, and highlight the need to determine the actual lifetime incidence of lung cancer among carriers, as well as the optimal starting age and interval for screening.
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– doi.org/10.1126/science.aec0473