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; Mary Y. Wu; 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, Mary Y. Wu, 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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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 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 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 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

Originalsprog	Engelsk
Tidsskrift	Cancer Discovery
Vol/bind	11
Udgave nummer	10
Sider (fra-til)	2456-2473
ISSN	2159-8274
DOI	https://doi.org/10.1158/2159-8290.CD-20-0725
Status	Udgivet - 2021

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10.1158/2159-8290.CD-20-0725

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487921/Licens: Ikke-specificeret

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Venkatesan, S., Angelova, M., Puttick, C., Zhai, H., Caswell, D. R., Lu, W., 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., 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, W, Dietzen, M, Galanos, P, Evangelou, K, Bellelli, R, Lim, EL, Watkins, TBK, Rowan, A, Teixeira, VH, Zhao, Y, Chen, H, Ngo, B, Zalmas, L, Al Bakir, M, Hobor, S, Grönroos, E, Pennycuick, A, Nigro, E, Campbell, BB, Brown, WL, Akarca, AU, Marafioti, T, Wu, MY, 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, bind 11, nr. 10, s. 2456-2473. https://doi.org/10.1158/2159-8290.CD-20-0725

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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 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 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 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 Wei-ting Lu 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 Lykourgos-panagiotis Zalmas 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 Wu, {Mary Y.} 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",

year = "2021",

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

language = "English",

volume = "11",

pages = "2456--2473",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research",

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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 - Wu, Mary Y.

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 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 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 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 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 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 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

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

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

M3 - Journal article

C2 - 33947663

SN - 2159-8274

VL - 11

SP - 2456

EP - 2473

JO - Cancer Discovery

JF - Cancer Discovery

IS - 10

ER -