Miguel Bronchud, Veteran Cancer Clinician and Researcher, shared on LinkedIn:
“Lung cancer in non smokers might rarely be the consequence of germ line mutations in the EGFR gene? USA 23andMe database, a population-scale biobank containing genomic data for 3.3 million participants, allowed to study the distribution, effects, and history of the haplotype containing T790.
On page 1208 in the recent SCIENCE issue, LoPiccolo et al. (Science 393, 1208 (2026)) report a population-scale analysis of a rare germline variant that is associated with high risk of lung cancer (without smoking cigarettes or cigars).
In addition to confirming its effects on lung cancer risk, the study uses historical and demographic data to uncover its history.
Two decades ago, a group of rare germline variants in the same stretch of DNA (haplotype) in the epidermal growth factor receptor (EGFR) gene were identified as risk factors for lung cancer
EGFR is a well-established oncogene with several common cancer-associated somatic (nongermline) variants that can be targeted with anticancer drugs .
It encodes a transmembrane receptor tyrosine kinase that promotes normal cell growth, but a single mutation on one chromosome in a somatic cell can lead to uncontrolled cell proliferation and cancer.
Nearly all somatic mutations in EGFR that have been documented in lung cancer tissue are lethal at the embryonic stage if they occur in germ cells. However, one of these variants, T790M, is not lethal during embryonic development.
And, to make this rare germ line mutation even more interesting , this variant occurs in families with incomplete penetrance, which means that some individuals who inherited T790M can reach old age without developing lung cancer.
In fact , T790M in somatic cells can contribute to resistance to targeted anticancer therapy .
As elegantly explained in an editorial in the same SCIENCE, LoPiccolo et al. (2026) very cleverly used the 23andMe database, a population-scale biobank containing genomic data for 3.3 million participants, to study the distribution, effects, and history of the haplotype containing T790M, which has been well characterized.
This type of study avoids some of the biases of studies that enroll participants on the basis of disease status, such as family studies or small case-control studies.
The scale of the database allows a different approach from the method typically used to characterize founder effects
Instead – HERE the Novelty – the authors gathered data from hundreds of individuals carrying a single copy of T790M (heterozygotes).
RESULTS: For most carriers of T790M, the variant resided on a long, shared segment of DNA that had the hallmarks of European ancestry. The authors also found that the neighboring genetic variants on this haplotype do not contribute to the effect of T790M.”
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