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Your search keyword '"Campbell, Brittany B"' showing total 3 results
Start Over Author "Campbell, Brittany B" Publisher american association for cancer research
3 results on '"Campbell, Brittany B"'

1. Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution

Author

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

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.

Published
2021

2. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution.

Author

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, 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, and Swanton C

Subjects
Animals, Cell Line, Tumor, Chromosomal Instability, DNA Replication, Female, Humans, Mice, APOBEC Deaminases genetics, Breast Neoplasms genetics, Carcinoma, Ductal genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
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 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. This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 American Association for Cancer Research.)

Published
2021
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3. Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.

Author

Campbell BB, Galati MA, Stone SC, Riemenschneider AN, Edwards M, Sudhaman S, Siddaway R, Komosa M, Nunes NM, Nobre L, Morrissy AS, Zatzman M, Zapotocky M, Joksimovic L, Kalimuthu SN, Samuel D, Mason G, Bouffet E, Morgenstern DA, Aronson M, Durno C, Malkin D, Maris JM, Taylor MD, Shlien A, Pugh TJ, Ohashi PS, Hawkins CE, and Tabori U

Subjects
Adult, Animals, Brain Neoplasms genetics, Cell Line, Tumor, Child, Colorectal Neoplasms genetics, Female, Glioma genetics, Global Health, Humans, Male, Mice, Mice, Inbred NOD, Mutation, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Colorectal Neoplasms drug therapy, Genetic Predisposition to Disease, Glioma drug therapy, Mitogen-Activated Protein Kinase Kinases genetics, Protein Kinase Inhibitors therapeutic use
Abstract

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations ( P = 10 -8 ). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo . Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers. This article is highlighted in the In This Issue feature, p. 1307 ., (©2021 American Association for Cancer Research.)

Published
2021
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