| Literature DB >> 33947663 |
Subramanian Venkatesan1,2, Mihaela Angelova1, Clare Puttick1, Haoran Zhai2, Deborah R Caswell1, Wei-Ting Lu1, Michelle Dietzen1,2,3, Panagiotis Galanos4, Konstantinos Evangelou5, Roberto Bellelli6, Emilia L Lim1,2, Thomas B K Watkins1, Andrew Rowan1, Vitor H Teixeira7, Yue Zhao8,9,10,11, Haiquan Chen8,9,10,11, Bryan Ngo12, Lykourgos-Panagiotis Zalmas13, Maise Al Bakir1, Sebastijan Hobor1, Eva Grönroos1, Adam Pennycuick7, Ersilia Nigro7, Brittany B Campbell1, William L Brown14,15, Ayse U Akarca16, Teresa Marafioti16, Mary Y Wu17, Michael Howell17, Simon J Boulton18, Cosetta Bertoli19, Tim R Fenton20, Robertus A M de Bruin19, Apolinar Maya-Mendoza4, Eric Santoni-Rugiu21,22, Robert E Hynds1,2, Vassilis G Gorgoulis5,23,24,25, Mariam Jamal-Hanjani2,26, Nicholas McGranahan2,3, Reuben S Harris14,15,27, Sam M Janes7, Jirina Bartkova4,28, Samuel F Bakhoum29,30, Jiri Bartek31,28, Nnennaya Kanu32, Charles Swanton.
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. ©2021 American Association for Cancer Research.Entities:
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Year: 2021 PMID： 33947663 PMCID： PMC8487921 DOI： 10.1158/2159-8290.CD-20-0725
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 38.272