Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution

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; Y. Wu Mary; 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

doi:10.1158/2159-8290.CD-20-0725

Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution

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 HoborEva Grönroos, Adam Pennycuick, Ersilia Nigro, Brittany B. Campbell, William L. Brown, Ayse U. Akarca, Teresa Marafioti, Y. Wu Mary, 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

Molecular Biology (BMBB)

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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 nonsmall 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 Gj 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.

Original language	English (US)
Pages (from-to)	2456-2473
Number of pages	18
Journal	Cancer discovery
Volume	11
Issue number	10
DOIs	https://doi.org/10.1158/2159-8290.CD-20-0725
State	Published - 2021

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1158/2159-8290.CD-20-0725

Find It

Find It at U of M Libraries

Cite this

Venkatesan, S., Angelova, M., Puttick, C., Zhai, H., Caswell, D. R., Lu, W. T., Dietzen, M., Galanos, P., Evangelou, K., Bellelli, R., Lim, E. L., Watkins, T. B. K., Rowan, A., Teixeira, V. H., Zhao, Y., Chen, H., Ngo, B., Zalmas, L. P., Al Bakir, M., ... Swanton, C. (2021). Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution. Cancer discovery, 11(10), 2456-2473. https://doi.org/10.1158/2159-8290.CD-20-0725

Venkatesan, S, Angelova, M, Puttick, C, Zhai, H, Caswell, DR, Lu, WT, Dietzen, M, Galanos, P, Evangelou, K, Bellelli, R, Lim, EL, Watkins, TBK, Rowan, A, Teixeira, VH, Zhao, Y, Chen, H, Ngo, B, Zalmas, LP, Al Bakir, M, Hobor, S, Grönroos, E, Pennycuick, A, Nigro, E, Campbell, BB, Brown, WL, Akarca, AU, Marafioti, T, Mary, YW, Howell, M, Boulton, SJ, Bertoli, C, Fenton, TR, De Bruin, RAM, Maya-Mendoza, A, Santoni-Rugiu, E, Hynds, RE, Gorgoulis, VG, Jamal-Hanjani, M, McGranahan, N, Harris, RS, Janes, SM, Bartkova, J, Bakhoum, SF, Bartek, J, Kanu, N & Swanton, C 2021, 'Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution', Cancer discovery, vol. 11, no. 10, pp. 2456-2473. https://doi.org/10.1158/2159-8290.CD-20-0725

@article{fec64a87714f426c8f4b94363f9b3496,

title = "Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution",

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 nonsmall 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 Gj 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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

doi = "10.1158/2159-8290.CD-20-0725",

language = "English (US)",

volume = "11",

pages = "2456--2473",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

TY - JOUR

T1 - 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

AU - Zhai, Haoran

AU - Caswell, Deborah R.

AU - Lu, Wei Ting

AU - Dietzen, Michelle

AU - Galanos, Panagiotis

AU - Evangelou, Konstantinos

AU - Bellelli, Roberto

AU - Lim, Emilia L.

AU - Watkins, Thomas B.K.

AU - Rowan, Andrew

AU - Teixeira, Vitor H.

AU - Zhao, Yue

AU - Chen, Haiquan

AU - Ngo, Bryan

AU - Zalmas, Lykourgos Panagiotis

AU - Al Bakir, Maise

AU - Hobor, Sebastijan

AU - Grönroos, Eva

AU - Pennycuick, Adam

AU - Nigro, Ersilia

AU - Campbell, Brittany B.

AU - Brown, William L.

AU - Akarca, Ayse U.

AU - Marafioti, Teresa

AU - Mary, Y. Wu

AU - Howell, Michael

AU - Boulton, Simon J.

AU - Bertoli, Cosetta

AU - Fenton, Tim R.

AU - De Bruin, Robertus A.M.

AU - Maya-Mendoza, Apolinar

AU - Santoni-Rugiu, Eric

AU - Hynds, Robert E.

AU - Gorgoulis, Vassilis G.

AU - Jamal-Hanjani, Mariam

AU - McGranahan, Nicholas

AU - Harris, Reuben S.

AU - Janes, Sam M.

AU - Bartkova, Jirina

AU - Bakhoum, Samuel F.

AU - Bartek, Jiri

AU - Kanu, Nnennaya

AU - Swanton, Charles

PY - 2021

Y1 - 2021

N2 - 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 nonsmall 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 Gj 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.

AB - 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 nonsmall 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 Gj 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.

UR - http://www.scopus.com/inward/record.url?scp=85111511923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85111511923&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-20-0725

DO - 10.1158/2159-8290.CD-20-0725

M3 - Article

C2 - 33947663

AN - SCOPUS:85111511923

SN - 2159-8274

VL - 11

SP - 2456

EP - 2473

JO - Cancer discovery

JF - Cancer discovery

IS - 10

ER -

Induction of apobec3 exacerbates dna replication stress and chromosomal instability in early breast and lung cancer evolution

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this