Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution

Subramanian Venkatesan, Mihaela Angelova, Clare Puttick, Haoran Zhai, Deborah R. Caswell, Wei Ting Lu, Michelle Dietzen, Panagiotis Galanos, Konstantinos Evangelou, Roberto Bellelli, Emilia L. Lim, Thomas B.K. Watkins, Andrew Rowan, Vitor H. Teixeira, Yue Zhao, Haiquan Chen, Bryan Ngo, Lykourgos Panagiotis Zalmas, Maise Al Bakir, Sebastijan HoborEva Grönroos, Adam Pennycuick, Ersilia Nigro, Brittany B. Campbell, William L. Brown, Ayse U. Akarca, Teresa Marafioti, Y. Wu Mary, Michael Howell, Simon J. Boulton, Cosetta Bertoli, Tim R. Fenton, Robertus A.M. De Bruin, Apolinar Maya-Mendoza, Eric Santoni-Rugiu, Robert E. Hynds, Vassilis G. Gorgoulis, Mariam Jamal-Hanjani, Nicholas McGranahan, Reuben S. Harris, Sam M. Janes, Jirina Bartkova, Samuel F. Bakhoum, Jiri Bartek, Nnennaya Kanu, Charles Swanton

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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 nonsmall 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 Gj 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.

Original languageEnglish (US)
Pages (from-to)2456-2473
Number of pages18
JournalCancer discovery
Issue number10
StatePublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research.


Dive into the research topics of 'Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution'. Together they form a unique fingerprint.

Cite this