Περίληψη:
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.
Συγγραφείς:
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
