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Cancer genomics

Developing multiple EGFR-mutant lung cancers

Nature Reviews Cancer volume 24, page 826 (2024)Cite this article

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In non-small cell lung cancer (NSCLC), the occurrence of multiple, independent tumours in the lungs of smokers is often attributed to field cancerization. In EGFR-mutant NSCLC, which occurs more frequently in non-smokers, the emergence of multiple primary tumours is more puzzling. In rare familial cases, heterozygous germline EGFR variants that lead to moderate (and thus germline-tolerable) EGFR activation, such as EGFRT790M, have been associated with NSCLC susceptibility. In individuals carrying these mutations, multiple tumours arise when somatic ‘canonical’ EGFR mutations with strong activation (most commonly L858R and E746–A750del) co-occur with the germline allele in cis. In a recent study published in Nature Cancer, Burr, Leshchiner, Costantino et al. set out to test if other genetic mechanisms are at play.

Four of these sporadic tumours displayed somatic mutations that were not shared with their matched normal tissues but had several shared mutations across lesions. Thus, these tumours arose neither completely independently, nor in the context of genetic predisposition, nor as clonally related metastasis. Instead, somatic mutation analysis suggested that the tumours derive from an ancestral clone that acquired somatic EGFR mutations during development. Progenitors of this clone were distributed throughout the adult body as part of normal development. In the lung, this developmental mosaicism of EGFR mutations predisposes individuals to develop NSCLC. This hypothesis was further supported by poly(G) genotyping, which allows estimation of the number of cell divisions that separate somatic cell populations.

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  1. Nature Reviews Cancer http://www.nature.com/nrc/

    Daniela Senft

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  1. Daniela Senft
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Correspondence to Daniela Senft.

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Senft, D. Developing multiple EGFR-mutant lung cancers. Nat Rev Cancer 24, 826 (2024). https://doi.org/10.1038/s41568-024-00773-9

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