journal contribution
posted on 2023-04-03, 23:29 authored by 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 Hobor, Eva Grönroos, Adam Pennycuick, Ersilia Nigro, Brittany B. Campbell, William L. Brown, Ayse U. Akarca, Teresa Marafioti, Mary Y. Wu, 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 Assessing APOBEC3 gene expression using immunohistochemical and bioinformatic approaches.
Funding
Wellcome Trust
KBVU
MRC-UCL
NCI
European Union's Horizon 2020
SARS-CoV-2
NKUA-SARG
NIH
NCI Breast Cancer SPORE
MSKCC
Danish Cancer Society
Novo Nordisk Foundation
Lundbeck foundation
Swedish Research council
Swedish Cancer Foundation
Cancer Research UK
UK Medical Research Council
European Union's Seventh Framework Programme
History
ARTICLE 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.
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
