Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution
Authors listSubramanian Venkatesan Mihaela Angelova Clare Puttick Haoran Zhai Deborah Caswell Wei-Ting Lu Michelle Dietzen Panagiotis Galanos Konstantinos Evangelou Roberto Bellelli Emilia Lim Tom Watkins Andrew Rowan Vitor H Teixeira Yue Zhao Haiquan Chen Bryan Ngo Lykourgos-Panagiotis Zalmas Maise Al Bakir Sebastijan Hobor Eva Gronroos Adam Pennycuick Ersilia Nigro Brittany B Campbell William L Brown Ayse U Akarca Teresa Marafioti Mary Wu Michael Howell Simon Boulton Cosetta Bertoli Tim R Fenton Robertus AM de Bruin Apolinar Maya-Mendoza Eric Santoni-Rugiu Rob 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 TRACERx Consortium
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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 DCIS, and in pre-invasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx pre-invasive to invasive 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 pre-invasive disease, providing fuel for selection early in cancer evolution.
Journal Cancer Discovery
Pages Epub ahead of print