APOBEC affects tumor evolution and age at onset of lung cancer in smokers

Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Kofi Ennu Johnson, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Frank Colon-Matos, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Marcin Imielinski, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris and Maria Teresa Landi ()
Additional contact information
Tongwu Zhang: National Cancer Institute
Jian Sang: National Cancer Institute
Phuc H. Hoang: National Cancer Institute
Wei Zhao: National Cancer Institute
Jennifer Rosenbaum: Westat
Kofi Ennu Johnson: New York Genome Center
Leszek J. Klimczak: National Institute of Environmental Health Sciences
John McElderry: National Cancer Institute
Alyssa Klein: National Cancer Institute
Christopher Wirth: The University of Manchester
Erik N. Bergstrom: University of California San Diego
Marcos Díaz-Gay: University of California San Diego
Raviteja Vangara: University of California San Diego
Frank Colon-Matos: National Cancer Institute
Amy Hutchinson: National Cancer Institute
Scott M. Lawrence: National Cancer Institute
Nathan Cole: National Cancer Institute
Bin Zhu: National Cancer Institute
Teresa M. Przytycka: National Institutes of Health
Jianxin Shi: National Cancer Institute
Neil E. Caporaso: National Cancer Institute
Robert Homer: Yale School of Medicine
Angela C. Pesatori: University of Milan
Dario Consonni: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Marcin Imielinski: New York Genome Center
Stephen J. Chanock: National Cancer Institute
David C. Wedge: The University of Manchester
Dmitry A. Gordenin: National Institute of Environmental Health Sciences
Ludmil B. Alexandrov: University of California San Diego
Reuben S. Harris: University of Texas Health San Antonio
Maria Teresa Landi: National Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.

Date: 2025
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DOI: 10.1038/s41467-025-59923-8

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