| Autor: |
Venkatesan, Subramanian Angelova, Mihaela Puttick, Clare and Zhai, Haoran Caswell, Deborah R. Lu, Wei-Ting Dietzen, Michelle Galanos, Panagiotis Evangelou, Konstantinos and Bellelli, Roberto Lim, Emilia L. Watkins, Thomas B. K. and Rowan, Andrew Teixeira, Vitor H. Zhao, Yue Chen, Haiquan and Ngo, Bryan Zalmas, Lykourgos-Panagiotis Al Bakir, Maise and Hobor, Sebastijan Gronroos, Eva Pennycuick, Adam Nigro, Ersilia Campbell, Brittany B. Brown, William L. Akarca, Ayse U. Marafioti, Teresa Wu, Mary Y. Howell, Michael and Boulton, Simon J. Bertoli, Cosetta Fenton, Tim R. de Bruin, Robertus A. M. Maya-Mendoza, Apolinar Santoni-Rugiu, Eric and Hynds, Robert E. Gorgoulis, Vassilis G. Jamal-Hanjani, Mariam and McGranahan, Nicholas Harris, Reuben S. Janes, Sam M. and Bartkova, Jirina Bakhoum, Samuel F. Bartek, Jiri Kanu, Nnennaya Swanton, Charles TRACERx Consortium |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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