Nonsmokers Also Face 25 Times Higher Lung Cancer Risk With T790M Genetic Variant

A genetic variant that raises the risk of lung cancer by about 25 times has been identified, even in people who do not smoke.

According to a study published in Science on the 17th (local time), people with the germline EGFR T790M variant had about 25 times the risk of lung cancer as those without it.

U.S. researchers used data from more than 10 million participants in 23andMe, a genetic analysis company. Of these, 641 carried the T790M variant, with a frequency of about 0.0000631.

An analysis of 3.37 million people of European ancestry found a clear association between the variant and lung cancer. The odds ratio (OR) was 25.18, with a 95% confidence interval of 13.5-46.78.

Compared with the odds ratio of 3.79 for smoking, the risk associated with the T790M variant was much higher. In particular, the odds ratio among carriers who had never smoked was 61.70, higher than the 10.59 among former smokers.

The median age at lung cancer diagnosis among variant carriers was 59.5 years, earlier than the 65 years among noncarriers.

The researchers assessed 18 cancer types, but found a significant association only with lung cancer. No association was found with the other 17 cancers or with noncancerous lung diseases.

The variant occurs in about 1 in 8,920 people in the United States, but is more common in the southern Appalachian region, at about 1 in 2,078. It was most common in the area along the Tennessee-Alabama border.

The researchers analyzed that the variant entered the United States through 18th-century English and Irish immigrants and then spread through a founder effect in the southern Appalachians in the early 19th century.

The genetic background of lung cancer in nonsmokers in Asia, including Korea, is more complex. The researchers explained that EGFR variants common in lung cancer in China mostly arise as somatic mutations and are not inherited through the germline.

The researchers suggested that people with a family history of lung cancer, multiple lung cancers or lung nodules, as well as young female patients who do not smoke, should pay attention to familial clustering and consider genetic counseling and testing when appropriate.