TY - JOUR
TI - Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal
Instability in Early Breast and Lung Cancer Evolution
AU - Venkatesan, Subramanian
AU - Angelova, Mihaela
AU - Puttick, Clare and
AU - Zhai, Haoran
AU - Caswell, Deborah R.
AU - Lu, Wei-Ting
AU - Dietzen,
AU - Michelle
AU - Galanos, Panagiotis
AU - Evangelou, Konstantinos and
AU - Bellelli, Roberto
AU - Lim, Emilia L.
AU - Watkins, Thomas B. K. and
AU - Rowan, Andrew
AU - Teixeira, Vitor H.
AU - Zhao, Yue
AU - Chen, Haiquan and
AU - Ngo, Bryan
AU - Zalmas, Lykourgos-Panagiotis
AU - Al Bakir, Maise and
AU - Hobor, Sebastijan
AU - Gronroos, Eva
AU - Pennycuick, Adam
AU - Nigro,
AU - Ersilia
AU - Campbell, Brittany B.
AU - Brown, William L.
AU - Akarca, Ayse
AU - U.
AU - Marafioti, Teresa
AU - Wu, Mary Y.
AU - Howell, Michael and
AU - Boulton, Simon J.
AU - Bertoli, Cosetta
AU - Fenton, Tim R.
AU - de Bruin,
AU - Robertus A. M.
AU - Maya-Mendoza, Apolinar
AU - Santoni-Rugiu, Eric and
AU - Hynds, Robert E.
AU - Gorgoulis, Vassilis G.
AU - Jamal-Hanjani, Mariam
AU - and McGranahan, Nicholas
AU - Harris, Reuben S.
AU - Janes, Sam M. and
AU - Bartkova, Jirina
AU - Bakhoum, Samuel F.
AU - Bartek, Jiri
AU - Kanu,
AU - Nnennaya
AU - Swanton, Charles
AU - TRACERx Consortium
JO - Cancer Discovery
PY - 2021
VL - 11
TODO - 10
SP - 2456-2473
PB - AMER ASSOC CANCER RESEARCH
SN - 2159-8274, 2159-8290
TODO - 10.1158/2159-8290.CD-20-0725
TODO - null
TODO - 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.
ER -