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2. Disentangling oncogenic amplicons in esophageal adenocarcinoma

Author

Ng, Alvin Wei Tian, McClurg, Dylan Peter, Wesley, Ben, Zamani, Shahriar A., Black, Emily, Miremadi, Ahmad, Giger, Olivier, Hoopen, Rogier ten, Devonshire, Ginny, Redmond, Aisling M., Grehan, Nicola, Jammula, Sriganesh, Blasko, Adrienn, Li, Xiaodun, Aparicio, Samuel, Tavaré, Simon, Nowicki-Osuch, Karol, and Fitzgerald, Rebecca C.

Published
2024
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3. Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation

Author

Fitzgerald, Rebecca C., Edwards, Paul A.W., Grehan, Nicola, Nutzinger, Barbara, Loreno, Christine, Redmond, Aisling M., Abbas, Sujath, Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Cheah, Calvin, Coles, Hannah, Millington, Curtis, Devonshire, Ginny, Eldridge, Matthew, Secrier, Maria, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J., Walker, Robert C., Grace, Ben L., Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Mahadeva, Ula, Goh, Vicky, Ciccarelli, Francesca D., Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L., Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B., Peters, Christopher J., Moorthy, Krishna, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, Petty, Russell D., Bartlet, Freddie, O'Neill, J. Robert, Yébenes Mayordomo, Marcos, Mitulović, Goran, Al Shboul, Sofian, Bedran, Georges, Faktor, Jakub, Hernychova, Lenka, Uhrik, Lukas, Gómez-Herranz, Maria, Kocikowski, Mikołaj, Vojtěšek, Bořivoj, Arends, Mark J., Hupp, Ted, and Alfaro, Javier Antonio

Published
2024
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5. Multicentre validation of CT grey-level co-occurrence matrix features for overall survival in primary oesophageal adenocarcinoma.

Author

O'Shea, Robert, Withey, Samuel J., Owczarczyk, Kasia, Rookyard, Christopher, Gossage, James, Godfrey, Edmund, Jobling, Craig, Parsons, Simon L., Skipworth, Richard J. E., Goh, Vicky, Fitzgerald, Rebecca C., Edwards, Paul A. W., Grehan, Nicola, Nutzinger, Barbara, Redmond, Aisling M., Abbas, Sujath, Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, and Miremadi, Ahmad

Subjects
OVERALL survival, ESOPHAGEAL tumors, DISEASE risk factors, ESOPHAGEAL cancer, SURVIVAL rate
Abstract

Background: Personalising management of primary oesophageal adenocarcinoma requires better risk stratification. Lack of independent validation of proposed imaging biomarkers has hampered clinical translation. We aimed to prospectively validate previously identified prognostic grey-level co-occurrence matrix (GLCM) CT features for 3-year overall survival. Methods: Following ethical approval, clinical and contrast-enhanced CT data were acquired from participants from five institutions. Data from three institutions were used for training and two for testing. Survival classifiers were modelled on prespecified variables ('Clinical' model: age, clinical T-stage, clinical N-stage; 'ClinVol' model: clinical features + CT tumour volume; 'ClinRad' model: ClinVol features + GLCM_Correlation and GLCM_Contrast). To reflect current clinical practice, baseline stage was also modelled as a univariate predictor ('Stage'). Discrimination was assessed by area under the receiver operating curve (AUC) analysis; calibration by Brier scores; and clinical relevance by thresholding risk scores to achieve 90% sensitivity for 3-year mortality. Results: A total of 162 participants were included (144 male; median 67 years [IQR 59, 72]; training, 95 participants; testing, 67 participants). Median survival was 998 days [IQR 486, 1594]. The ClinRad model yielded the greatest test discrimination (AUC, 0.68 [95% CI 0.54, 0.81]) that outperformed Stage (ΔAUC, 0.12 [95% CI 0.01, 0.23]; p =.04). The Clinical and ClinVol models yielded comparable test discrimination (AUC, 0.66 [95% CI 0.51, 0.80] vs. 0.65 [95% CI 0.50, 0.79]; p >.05). Test sensitivity of 90% was achieved by ClinRad and Stage models only. Conclusions: Compared to Stage, multivariable models of prespecified clinical and radiomic variables yielded improved prediction of 3-year overall survival. Clinical relevance statement: Previously identified radiomic features are prognostic but may not substantially improve risk stratification on their own. Key Points: • Better risk stratification is needed in primary oesophageal cancer to personalise management. • Previously identified CT features—GLCM_Correlation and GLCM_Contrast—contain incremental prognostic information to age and clinical stage. • Compared to staging, multivariable clinicoradiomic models improve discrimination of 3-year overall survival. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype

Author

Varešlija, Damir, Ward, Elspeth, Purcell, Siobhan P., Cosgrove, Nicola S., Cocchiglia, Sinéad, O’Halloran, Philip J., Charmsaz, Sara, Bane, Fiona T., Brett, Francesca M., Farrell, Michael, Cryan, Jane, Beausang, Alan, Hudson, Lance, Turnbul, Arran K., Dixon, J. Michael, Hill, Arnold D. K., Priedigkeit, Nolan, Oesterreich, Steffi, Lee, Adrian V., Sims, Andrew H., Redmond, Aisling M., Carroll, Jason S., and Young, Leonie S.

Published
2021
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7. Pervasive lesion segregation shapes cancer genome evolution

Author

Aitken, Sarah J., Anderson, Craig J., Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F., Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd V., Davies, Susan E., Drews, Ruben M., Ewing, Ailith, Kaiser, Vera B., Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M., Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D., Semple, Colin A., López-Bigas, Núria, Flicek, Paul, Odom, Duncan T., and Taylor, Martin S.

Published
2020
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11. Figure 3 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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12. Supplementary Table S4 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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13. Supplementary Figures from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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14. Figure 2 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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15. Figure 5 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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16. Figure 1 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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17. Figure 4 from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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18. Data from Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, primary, Cheung, Tik Shing, primary, Black, Emily L., primary, Masqué-Soler, Neus, primary, Devonshire, Ginny, primary, Redmond, Aisling M., primary, Freeman, Adam, primary, di Pietro, Massimilliano, primary, Pilonis, Nastazja, primary, Januszewicz, Wladyslaw, primary, O'Donovan, Maria, primary, Tavaré, Simon, primary, Shields, Jacqueline D., primary, and Fitzgerald, Rebecca C., primary

Published
2023
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19. Supplementary Figures from Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors

Author

Varešlija, Damir, primary, McBryan, Jean, primary, Fagan, Ailís, primary, Redmond, Aisling M., primary, Hao, Yuan, primary, Sims, Andrew H., primary, Turnbull, Arran, primary, Dixon, J.M., primary, Ó Gaora, Peadar, primary, Hudson, Lance, primary, Purcell, Siobhan, primary, Hill, Arnold D.K., primary, and Young, Leonie S., primary

Published
2023
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21. Supplementary Tables from Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors

Author

Varešlija, Damir, primary, McBryan, Jean, primary, Fagan, Ailís, primary, Redmond, Aisling M., primary, Hao, Yuan, primary, Sims, Andrew H., primary, Turnbull, Arran, primary, Dixon, J.M., primary, Ó Gaora, Peadar, primary, Hudson, Lance, primary, Purcell, Siobhan, primary, Hill, Arnold D.K., primary, and Young, Leonie S., primary

Published
2023
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22. Single-cell RNA sequencing unifies developmental programs of Esophageal and Gastric Intestinal Metaplasia.

Author

Nowicki-Osuch, Karol, primary, Zhuang, Lizhe, additional, Cheung, Tik Shing, additional, Black, Emily L., additional, Masque-Soler, Neus, additional, Devonshire, Ginny, additional, Redmond, Aisling M., additional, Freeman, Adam, additional, di Pietro, Massimilliano, additional, Pilonis, Nastazja, additional, Januszewicz, Wladyslaw, additional, O'Donovan, Maria, additional, Tavare, Simon, additional, Shields, Jacqueline D., additional, and Fitzgerald, Rebecca C., additional

Published
2023
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23. Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma.

Author

Abbas, Sujath, Pich, Oriol, Devonshire, Ginny, Zamani, Shahriar A., Katz-Summercorn, Annalise, Killcoyne, Sarah, Cheah, Calvin, Nutzinger, Barbara, Grehan, Nicola, Lopez-Bigas, Nuria, Edwards, Paul A. W., Fidziukiewicz, Elwira, Redmond, Aisling M., Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, and Coles, Hannah

Subjects
DNA repair, BARRETT'S esophagus, ADENOCARCINOMA, NUCLEOTIDE sequencing, CARCINOGENESIS, DNA damage
Abstract

A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma. It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett's Oesophagus, as well as their prognostic associations. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Serial circulating tumor DNA detection using a personalized, tumor-informed assay in esophageal adenocarcinoma patients following resection

Author

Ococks, Emma, Sharma, Shruti, Ng, Alvin Wei Tian, Consortium, OCCAMS, Aleshin, Alexey, Fitzgerald, Rebecca C, Smyth, Elizabeth, Edwards, Paul AW, Grehan, Nicola, Nutzinger, Barbara, Fidziukiewicz, Elwira, Redmond, Aisling M, Northrop, Alex, Abbas, Sujath, Smyth, Elizabeth C, O���Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Grantham, Amber, Cheah, Calvin, Coles, Hannah, Flint, Connor, Eldridge, Matthew, Secrier, Maria, Devonshire, Ginny, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H, Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J, Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R, Bagwan, Izhar, Save, Vicki, Skipworth, Richard JE, Hupp, Ted R, O���Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J, Walker, Robert C, Grace, Ben L, Lagergren, Jesper, Gossage, James, Mahadeva, Ula, Davies, Andrew, Chang, Fuju, Goh, Vicky, Ciccarelli, Francesca D, Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L, Parsons, Simon L, Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B, Moorthy, Krishna, Peters, Christopher J, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, and Petty, Russell D

Subjects
Genome Integrity & Repair, Gene Expression, Genetics & Genomics, Computational & Systems Biology
Abstract

No description supplied

Published
2021
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27. Pervasive lesion segregation shapes cancer genome evolution

Author

Aitken, Sarah J., Anderson, Craig J., Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F., Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd V., Davies, Susan E., Drews, Ruben M., Ewing, Ailith, Kaiser, Vera B., Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M., Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D., Flicek, Paul, López-Bigas, Núria, Odom, Duncan T., Semple, Colin A., Taylor, Martin S., Aitken, Sarah [0000-0002-1897-4140], Connor, Frances [0000-0003-2858-9411], and Apollo - University of Cambridge Repository

Subjects
Male, DNA Repair, Transcription, Genetic, Cell division, Genome, chemistry.chemical_compound, Mice, 0302 clinical medicine, Chromosome Segregation, Neoplasms, Cancer genomics, Genetics, 0303 health sciences, Multidisciplinary, Liver Neoplasms, Cell cycle, 3. Good health, ErbB Receptors, raf Kinases, medicine.symptom, Signal Transduction, DNA Replication, Tumour heterogeneity, DNA repair, Base pair, DNA damage, Sister chromatid exchange, Biology, Lesion, Evolution, Molecular, 03 medical and health sciences, medicine, Animals, Humans, Allele, Selection, Genetic, Alleles, 030304 developmental biology, DNA replication, Cancer, DNA adducts, medicine.disease, Nucleotide excision repair, chemistry, Mutation, ras Proteins, Sister Chromatid Exchange, DNA, 030217 neurology & neurosurgery
Abstract

SummaryCancers arise through the acquisition of oncogenic mutations and grow through clonal expansion1, 2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can generate multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

Published
2019
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28. Pervasive lesion segregation shapes cancer genome evolution

Author

Aitken, Sarah J., primary, Anderson, Craig J., additional, Connor, Frances, additional, Pich, Oriol, additional, Sundaram, Vasavi, additional, Feig, Christine, additional, Rayner, Tim F., additional, Lukk, Margus, additional, Aitken, Stuart, additional, Luft, Juliet, additional, Kentepozidou, Elissavet, additional, Arnedo-Pac, Claudia, additional, Beentjes, Sjoerd, additional, Davies, Susan E., additional, Drews, Ruben M., additional, Ewing, Ailith, additional, Kaiser, Vera B., additional, Khamseh, Ava, additional, López-Arribillaga, Erika, additional, Redmond, Aisling M., additional, Santoyo-Lopez, Javier, additional, Sentís, Inés, additional, Talmane, Lana, additional, Yates, Andrew D., additional, Semple, Colin A., additional, López-Bigas, Núria, additional, Flicek, Paul, additional, Odom, Duncan T., additional, and Taylor, Martin S., additional

Published
2019
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31. Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation

Author

O'Neill, J. Robert, Yébenes Mayordomo, Marcos, Mitulović, Goran, Al Shboul, Sofian, Bedran, Georges, Faktor, Jakub, Hernychova, Lenka, Uhrik, Lukas, Gómez-Herranz, Maria, Kocikowski, Mikołaj, Save, Vicki, Vojtěšek, Bořivoj, Arends, Mark J., Fitzgerald, Rebecca C., Edwards, Paul A.W., Grehan, Nicola, Nutzinger, Barbara, Loreno, Christine, Redmond, Aisling M., Abbas, Sujath, Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Cheah, Calvin, Coles, Hannah, Millington, Curtis, Devonshire, Ginny, Eldridge, Matthew, Secrier, Maria, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J., Walker, Robert C., Grace, Ben L., Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Mahadeva, Ula, Goh, Vicky, Ciccarelli, Francesca D., Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L., Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B., Peters, Christopher J., Moorthy, Krishna, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, Petty, Russell D., Bartlet, Freddie, Hupp, Ted, and Alfaro, Javier Antonio

Abstract

Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNA-seq and proteomic data from seven patients and further integrated these data with a cohort of EAC RNA-seq data (n = 264 patients), EAC whole-genome sequencing (n = 454 patients), and external published datasets. We quantified protein expression from 5879 genes in EAC and patient-matched normal tissues. Several biomarker candidates with EAC-selective expression were identified, including the transmembrane protein GPA33. We further verified the EAC-enriched expression of GPA33 in an external cohort of 115 patients and confirm this as an attractive diagnostic and therapeutic target. To further extend the insights gained from our proteomic data, an integrated analysis of protein and RNA expression in EAC and normal tissues revealed several genes with poorly correlated protein and RNA abundance, suggesting posttranscriptional regulation of protein expression. These outlier genes, including SLC25A30, TAOK2, and AGMAT, only rarely demonstrated somatic mutation, suggesting post-transcriptional drivers for this EAC-specific phenotype. AGMAT was demonstrated to be overexpressed at the protein level in EAC compared to adjacent normal tissues with an EAC-selective, post-transcriptional mechanism of regulation of protein abundance proposed. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, posttranscriptional regulation of protein expression, which may be an exploitable vulnerability.

Published
2024
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32. Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors

Author

Varešlija, Damir, primary, McBryan, Jean, additional, Fagan, Ailís, additional, Redmond, Aisling M., additional, Hao, Yuan, additional, Sims, Andrew H., additional, Turnbull, Arran, additional, Dixon, J.M., additional, Ó Gaora, Peadar, additional, Hudson, Lance, additional, Purcell, Siobhan, additional, Hill, Arnold D.K., additional, and Young, Leonie S., additional

Published
2016
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36. Pervasive lesion segregation shapes cancer genome evolution

Author

Aitken, Sarah J, Anderson, Craig J, Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F, Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd, Davies, Susan E, Drews, Ruben M, Ewing, Ailith, Kaiser, Vera B, Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M, Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D, Semple, Colin A, López-Bigas, Núria, Flicek, Paul, Odom, Duncan T, and Taylor, Martin S

Subjects
DNA Replication, Male, Genome, DNA Repair, Transcription, Genetic, Liver Neoplasms, 3. Good health, ErbB Receptors, Evolution, Molecular, Mice, Chromosome Segregation, Neoplasms, Mutation, ras Proteins, Animals, Humans, raf Kinases, Selection, Genetic, Sister Chromatid Exchange, Alleles, Signal Transduction
Abstract

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

37. Analysis of HER2 genomic binding in breast cancer cells identifies a global role in direct gene regulation

Author

Redmond, Aisling M, Omarjee, Soleilmane, Chernukhin, Igor, Le Romancer, Muriel, and Carroll, Jason S

Subjects
Transcriptional Activation, Receptor, ErbB-2, Breast Neoplasms, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, Histones, Enhancer Elements, Genetic, Cell Line, Tumor, Humans, Female, Nucleotide Motifs, skin and connective tissue diseases, neoplasms, Protein Binding
Abstract

HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in two breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF and have identified a de novo motif at HER2 binding sites. Over 2,000 HER2 binding sites are found in both breast cancer cell lines after EGF treatment, and according to pathway analysis, these binding sites were enriched near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a small subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners in the nucleus. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.

38. A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division

Author

Fanni Gergely, Jasmin Mangei, John C. Marioni, Patrice Mascalchi, Chris Bakal, Duncan T. Odom, Christina Ernst, Alexis R. Barr, Aisling M. Redmond, Vicky Bousgouni, Lovorka Stojic, Aaron T. L. Lun, Stojic, Lovorka [0000-0001-6691-3396], Lun, Aaron T. L. [0000-0002-3564-4813], Redmond, Aisling M. [0000-0001-9070-1780], Barr, Alexis R. [0000-0002-6684-8114], Bakal, Chris [0000-0002-0413-6744], Odom, Duncan T. [0000-0001-6201-5599], Gergely, Fanni [0000-0002-2441-8095], Apollo - University of Cambridge Repository, Lun, Aaron TL [0000-0002-3564-4813], Redmond, Aisling M [0000-0001-9070-1780], Barr, Alexis R [0000-0002-6684-8114], Odom, Duncan T [0000-0001-6201-5599], and Lun, Aaron T L [0000-0002-3564-4813]

Subjects
0301 basic medicine, binding, Cell division, General Physics and Astronomy, comparative genomics, 13, 14, 631/337/641/1655, Transcriptome, Chromosome segregation, 0302 clinical medicine, RNA interference, lcsh:Science, 0303 health sciences, Multidisciplinary, 030302 biochemistry & molecular biology, High-throughput screening, Cell biology, Multidisciplinary Sciences, spindle-assembly checkpoint, 631/337/384/2568, Science & Technology - Other Topics, RNA Interference, RNA, Long Noncoding, Cell Division, Cell type, Science, Mitosis, gene repression, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 38, 38/91, 14/32, 03 medical and health sciences, Microtubule, expression, 38/89, 631/208/200, Humans, 030304 developmental biology, Science & Technology, microtubule organization, Proteins, General Chemistry, mitotic block, 49, High-Throughput Screening Assays, Gene regulation, 030104 developmental biology, tubulin, 14/63, Long non-coding RNAs, lcsh:Q, tppp/p25, 631/1647/2163, protein, 030217 neurology & neurosurgery, Cytokinesis, HeLa Cells
Abstract

Genome stability relies on proper coordination of mitosis and cytokinesis, where dynamic microtubules capture and faithfully segregate chromosomes into daughter cells. With a high-content RNAi imaging screen targeting more than 2,000 human lncRNAs, we identify numerous lncRNAs involved in key steps of cell division such as chromosome segregation, mitotic duration and cytokinesis. Here, we provide evidence that the chromatin-associated lncRNA, linc00899, leads to robust mitotic delay upon its depletion in multiple cell types. We perform transcriptome analysis of linc00899-depleted cells and identify the neuronal microtubule-binding protein, TPPP/p25, as a target of linc00899. We further show that linc00899 binds TPPP/p25 and suppresses its transcription. In cells depleted of linc00899, upregulation of TPPP/p25 alters microtubule dynamics and delays mitosis. Overall, our comprehensive screen uncovers several lncRNAs involved in genome stability and reveals a lncRNA that controls microtubule behaviour with functional implications beyond cell division., Long noncoding RNAs (lncRNAs) regulate key steps of cell division. Here, the authors perform a comprehensive RNAi imaging screen targeting more than 2,000 human lncRNAs, and suggest a role of chromatin-associated linc00899 in regulation of cell division by suppressing the transcription of microtubule-binding protein TPPP/p25.

Published
2019

39. Analysis of HER2 genomic binding in breast cancer cells identifies a global role in direct gene regulation

Author

Igor Chernukhin, Muriel Le Romancer, Soleilmane Omarjee, Aisling M. Redmond, Jason S. Carroll, Redmond, Aisling M [0000-0001-9070-1780], Apollo - University of Cambridge Repository, Bodescot, Myriam, Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), University of Cambridge [UK] (CAM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was funded by Cancer Research UK (JSC, Core funding), European Research Council (JSC, 646876) and Fondation ARC Cancer (MLR, Core Funding), Region Rhone Alpes (SO) and La Ligue Contre le Cancer (SO)., and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Receptor, ErbB-2, Gene Expression, Proximity ligation assay, Plasma protein binding, Receptor tyrosine kinase, Histones, Binding Analysis, Database and Informatics Methods, 0302 clinical medicine, Breast Tumors, Medicine and Health Sciences, skin and connective tissue diseases, Regulation of gene expression, Multidisciplinary, biology, Chromosome Biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Chromatin, Cell biology, 3. Good health, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, Oncology, 030220 oncology & carcinogenesis, Medicine, Cell lines, Epigenetics, Female, Signal transduction, Biological cultures, Sequence Analysis, medicine.drug, Research Article, Protein Binding, Cell Binding, Transcriptional Activation, Cell Physiology, Bioinformatics, Science, BT474 cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Lapatinib, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Sequence Motif Analysis, Cell Line, Tumor, Breast Cancer, medicine, Genetics, Humans, Gene Regulation, Binding site, Nucleotide Motifs, neoplasms, Chemical Characterization, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, Research and analysis methods, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], biology.protein
Abstract

International audience; HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in two breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF and have identified a de novo motif at HER2 binding sites. Over 2,000 HER2 binding sites are found in both breast cancer cell lines after EGF treatment, and according to pathway analysis, these binding sites were enriched near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a small subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners in the nucleus. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.

Published
2019
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40. Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients.

Author

Dillon MF, Stafford AT, Kelly G, Redmond AM, McIlroy M, Crotty TB, McDermott E, Hill AD, and Young LS

Subjects
Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms mortality, Carcinoma drug therapy, Carcinoma metabolism, Carcinoma mortality, Cell Nucleus drug effects, Cohort Studies, Disease Progression, Female, Humans, Mitogen-Activated Protein Kinase 3 metabolism, Prognosis, Receptor, ErbB-2 metabolism, Survival Analysis, Tamoxifen therapeutic use, Tissue Distribution, Transcription Factors metabolism, Treatment Outcome, Breast Neoplasms diagnosis, Carcinoma diagnosis, Cell Nucleus metabolism, Cyclooxygenase 2 physiology, Receptor, ErbB-2 physiology, Tamoxifen adverse effects
Abstract

Cyclooxygenase-2 (COX-2) is associated with breast tumour progression. Clinical and molecular studies implicate human epidermal growth factor receptor 2 (HER2) in the regulation of COX-2 expression. Recent reports raise the possibility that HER2 could mediate these effects through direct transcriptional mechanisms. The relationship between HER2 and COX-2 was investigated in a cohort of breast cancer patients with or without endocrine treatment. A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for HER2, ERK1/2, polyoma enhancer activator 3 (PEA3) and COX-2 expression. Subcellular localisation of HER2 was assessed by immunofluorescence and confocal microscopy. Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen. COX-2 expression associated with both membranous and nuclear expression of HER2 (P=0.0033 and P<0.00001 respectively). No association was detected between COX-2 and either ERK1/2 or PEA3 (P=0.7 and P=0.3 respectively). None of the markers were found to be independently prognostic. Membrane HER2, nuclear HER2 and COX-2, however, were all found to predict poor disease-free survival in patients on endocrine treatment (P=0.0017, P=0.0003 and P=0.0202 respectively). Moreover, patients who were positive for COX-2 predicted adverse effects of tamoxifen (P=0.0427). These clinical ex vivo data are consistent with molecular observations that HER2 can regulate COX-2 expression through direct transcriptional mechanisms. COX-2 expression correlates with disease progression on endocrine treatment. This study supports a role for COX-2 as a predictor of adverse effects of tamoxifen in breast cancer patients.

Published
2008
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