Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers

Khandekar, A.; Hoang, P. H.; Luebeck, J.; Diaz-Gay, M.; Zhao, W.; McElderry, J. P.; Hartman, C.; Miraftab, M.; Lee, O. W.; Barnao, K. M.; Bergstrom, E. N.; Yang, Y.; Nowak, M. A.; Rothman, N.; Homer, R.; Yang, S.-R.; Lan, Q.; Wedge, D. C.; Yang, L.; Chanock, S. J.; Zhang, T.; Alexandrov, L. B.; Landi, M. T.

doi:10.1101/2025.06.03.657117

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bioRxiv · 10.1101/2025.06.03.657117

Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers

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Abstract

The role of extrachromosomal DNA (ecDNA) in lung cancer, particularly in subjects who never smoked (LCINS), remains unclear. Examination of over 1200 whole-genome-sequenced lung cancers identified ecDNA in 18.9% of patients. Recurrent amplification of MDM2 and other oncogenes via ecDNA possibly drives a LCINS subset. Tumors harboring ecDNA showed worse overall survival than tumors harboring other focal amplifications. A strong association with whole-genome doubling suggests most ecDNA reflects genomic instability in treatment-naive lung cancer.

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Khandekar, A., Hoang, P. H., Luebeck, J., Diaz-Gay, M., Zhao, W., McElderry, J. P., Hartman, C., Miraftab, M., Lee, O. W., Barnao, K. M., Bergstrom, E. N., Yang, Y., Nowak, M. A., Rothman, N., Homer, R., Yang, S.-R., Lan, Q., Wedge, D. C., Yang, L., Chanock, S. J., Zhang, T., Alexandrov, L. B., Landi, M. T.. 2025-06-07. Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers. https://doi.org/10.1101/2025.06.03.657117

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