1. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution
- Author
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Wei-Ting Lu, Lykourgos-Panagiotis Zalmas, Konstantinos Evangelou, Ersilia Nigro, Vitor H. Teixeira, Mary Y. Wu, Robertus A.M. de Bruin, Ayse U. Akarca, Nicholas McGranahan, Michelle Dietzen, Panagiotis Galanos, Adam Pennycuick, Clare Puttick, Eric Santoni-Rugiu, Bryan Ngo, Jiri Bartek, William L. Brown, Sam M. Janes, Haoran Zhai, Deborah R. Caswell, Sebastijan Hobor, Cosetta Bertoli, Emilia L. Lim, Tim R. Fenton, Mariam Jamal-Hanjani, Reuben S. Harris, Roberto Bellelli, Brittany B. Campbell, Mihaela Angelova, Samuel F. Bakhoum, Eva Grönroos, Yue Zhao, Thomas B.K. Watkins, Robert E. Hynds, Vassilis G. Gorgoulis, Apolinar Maya-Mendoza, Maise Al Bakir, Charles Swanton, Teresa Marafioti, Andrew Rowan, Nnennaya Kanu, Michael Howell, Jirina Bartkova, Simon J. Boulton, Subramanian Venkatesan, Haiquan Chen, Venkatesan, S., Angelova, M., Puttick, C., Zhai, H., Caswell, D. R., Lu, W. -T., Dietzen, M., Galanos, P., Evangelou, K., Bellelli, R., Lim, E. L., Watkins, T. B. K., Rowan, A., Teixeira, V. H., Zhao, Y., Chen, H., Ngo, B., Zalmas, L. -P., Al Bakir, M., Hobor, S., Gronroos, E., Pennycuick, A., Nigro, E., Campbell, B. B., Brown, W. L., Akarca, A. U., Marafioti, T., Mary, Y. W., Howell, M., Boulton, S. J., Bertoli, C., Fenton, T. R., De Bruin, R. A. M., Maya-Mendoza, A., Santoni-Rugiu, E., Hynds, R. E., Gorgoulis, V. G., Jamal-Hanjani, M., Mcgranahan, N., Harris, R. S., Janes, S. M., Bartkova, J., Bakhoum, S. F., Bartek, J., Kanu, N., and Swanton, C.
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DNA Replication ,Lung Neoplasms ,viruses ,Breast Neoplasms ,Biology ,Article ,RC0254 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Chromosomal Instability ,Chromosome instability ,medicine ,Animals ,Humans ,APOBEC Deaminases ,APOBEC Deaminase ,QP506 ,Lung cancer ,Gene ,Mitosis ,030304 developmental biology ,0303 health sciences ,Animal ,DNA replication ,Chromosome ,Cancer ,biochemical phenomena, metabolism, and nutrition ,Cell cycle ,medicine.disease ,3. Good health ,Carcinoma, Ductal ,Lung Neoplasm ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Breast Neoplasm ,Human - Abstract
APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. Significance: This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution. This article is highlighted in the In This Issue feature, p. 2355
- Published
- 2020
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