Vankatesan, Subramanian, Angelova, Mihaela, Puttick, Clare, Zhai, Haoran, Caswell, Deborah, Lu, Wei-Ting, Dietzen, Michelle, Galanos, Panagiotis, Evangelou, Konstantinos, Bellelli, Roberto, and others. (2021) Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution. Cancer Discovery, . ISSN 2159-8274. E-ISSN 2159-8290. (doi:10.1158/2159-8290.CD-20-0725) (KAR id:87938)
|
PDF
Author's Accepted Manuscript
Language: English |
|
|
Download this file (PDF/7MB) |
Preview |
| Request a format suitable for use with assistive technology e.g. a screenreader | |
| Official URL: http://dx.doi.org/10.1158/2159-8290.CD-20-0725 |
|
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 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.
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1158/2159-8290.CD-20-0725 |
| Uncontrolled keywords: | APOBEC, non-small cell lung cancer, breast cancer, intratumor heterogeneity, chromosomal instability, pre-invasive |
| Subjects: |
Q Science > QP Physiology (Living systems) > QP506 Molecular biology R Medicine > RC Internal medicine > RC254 Neoplasms. Tumors. Oncology |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Depositing User: | Tim Fenton |
| Date Deposited: | 06 May 2021 11:13 UTC |
| Last Modified: | 05 Apr 2022 22:08 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/87938 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Fenton, Tim R..
| Creator's ORCID: |
 https://orcid.org/0000-0002-4737-8233
|
|---|---|
| CReDIT Contributor Roles: |
- Link to SensusAccess
- Export to:
- RefWorks
- EPrints3 XML
- BibTeX
- CSV
- Depositors only (login required):
Altmetric
Altmetric
