@article{3031950,
    title = "Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal
Instability in Early Breast and Lung Cancer Evolution",
    author = "Venkatesan, Subramanian and Angelova, Mihaela and Puttick, Clare and and Zhai, Haoran and Caswell, Deborah R. and Lu, Wei-Ting and Dietzen, and Michelle and Galanos, Panagiotis and Evangelou, Konstantinos and and Bellelli, Roberto and Lim, Emilia L. and Watkins, Thomas B. K. and and Rowan, Andrew and Teixeira, Vitor H. and Zhao, Yue and Chen, Haiquan and and Ngo, Bryan and Zalmas, Lykourgos-Panagiotis and Al Bakir, Maise and and Hobor, Sebastijan and Gronroos, Eva and Pennycuick, Adam and Nigro, and Ersilia and Campbell, Brittany B. and Brown, William L. and Akarca, Ayse and U. and Marafioti, Teresa and Wu, Mary Y. and Howell, Michael and and Boulton, Simon J. and Bertoli, Cosetta and Fenton, Tim R. and de Bruin, and Robertus A. M. and Maya-Mendoza, Apolinar and Santoni-Rugiu, Eric and and Hynds, Robert E. and Gorgoulis, Vassilis G. and Jamal-Hanjani, Mariam and and McGranahan, Nicholas and Harris, Reuben S. and Janes, Sam M. and and Bartkova, Jirina and Bakhoum, Samuel F. and Bartek, Jiri and Kanu, and Nnennaya and Swanton, Charles and TRACERx Consortium",
    journal = "Cancer Discovery",
    year = "2021",
    volume = "11",
    number = "10",
    pages = "2456-2473",
    publisher = "AMER ASSOC CANCER RESEARCH",
    issn = "2159-8274, 2159-8290",
    doi = "10.1158/2159-8290.CD-20-0725",
    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 G(1) 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."
}