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

Zhang, T.
; 
Sang, J.
; 
Hoang, P. H.
; 
Zhao, W.
; 
Rosenbaum, J.
; 
Johnson, K. E.
; 
Klimczak, L. J.
; 
McElderry, J.
; 
Klein, A.
; 
Wirth, C.
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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.
Authors
Zhang, T.
Sang, J.
Hoang, P. H.
Zhao, W.
Rosenbaum, J.
Johnson, K. E.
Klimczak, L. J.
McElderry, J.
Klein, A.
Wirth, C.
Bergstrom, E. N.
Díaz-Gay, M.
Vangara, R.
Colon-Matos, F.
Hutchinson, A.
Lawrence, S. M.
Cole, N.
Zhu, B.
Przytycka, T. M.
Shi, J.
Caporaso, N. E.
Homer, R.
Pesatori, A. C.
Consonni, D.
Imielinski, M.
Chanock, S. J.
Wedge, D. C.
Gordenin, D. A.
Alexandrov, L. B.
Harris, R. S.
Landi, M. T.
Affiliation
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Westat, Rockville, MD, USA. New York Genome Center, New York, USA. Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Manchester Cancer Research Centre, The University of Manchester, Manchester, UK. Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA. Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA. Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, TX, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. landim@mail.nih.gov.
Description
Date
2025
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All Paterson Institute for Cancer Research
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Zhang T, Sang J, Hoang PH, Zhao W, Rosenbaum J, Johnson KE, et al. APOBEC affects tumor evolution and age at onset of lung cancer in smokers. Nature communications. 2025 May 21;16(1):4711. PubMed PMID: 40394004. Pubmed Central PMCID: PMC12092836 in io9, LLC. His spouse is an employee of Biotheranostics, Inc. L.B.A. is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. E.N.B. and L.B.A. declare U.S. provisional patent applications with serial numbers 63/289,601 and 63/269,033. L.B.A. also declares U.S. provisional patent applications with serial numbers: 63/366,392; 63/367,846; and 63/412,835. All other authors declare no competing interests. Epub 2025/05/21. eng.
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https://christie.openrepository.com/handle/10541/627512
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