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3. Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer

Author

Parkes, Eileen E., Savage, Kienan I., Lioe, Tong, Boyd, Clinton, Halliday, Sophia, Walker, Steven M., Lowry, Keith, Knight, Laura, Buckley, Niamh E., Grogan, Andrena, Logan, Gemma E., Clayton, Alison, Hurwitz, Jane, Kirk, Stephen J., Xu, Jiamei, Sidi, Fatima Abdullahi, Humphries, Matthew P., Bingham, Victoria, James, Jaqueline A., James, Colin R., Paul Harkin, D., Kennedy, Richard D., and McIntosh, Stuart A.

Published
2022
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7. Data from Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors

Author

Lappin, Katrina M., primary, Barros, Eliana M., primary, Jhujh, Satpal S., primary, Irwin, Gareth W., primary, McMillan, Hayley, primary, Liberante, Fabio G., primary, Latimer, Cheryl, primary, La Bonte, Melissa J., primary, Mills, Ken I., primary, Harkin, D. Paul, primary, Stewart, Grant S., primary, and Savage, Kienan I., primary

Published
2023
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9. Supplementary Table from Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors

Author

Lappin, Katrina M., primary, Barros, Eliana M., primary, Jhujh, Satpal S., primary, Irwin, Gareth W., primary, McMillan, Hayley, primary, Liberante, Fabio G., primary, Latimer, Cheryl, primary, La Bonte, Melissa J., primary, Mills, Ken I., primary, Harkin, D. Paul, primary, Stewart, Grant S., primary, and Savage, Kienan I., primary

Published
2023
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11. Supplementary Data from Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors

Author

Lappin, Katrina M., primary, Barros, Eliana M., primary, Jhujh, Satpal S., primary, Irwin, Gareth W., primary, McMillan, Hayley, primary, Liberante, Fabio G., primary, Latimer, Cheryl, primary, La Bonte, Melissa J., primary, Mills, Ken I., primary, Harkin, D. Paul, primary, Stewart, Grant S., primary, and Savage, Kienan I., primary

Published
2023
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13. Supplementary Figure Legends from BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Author

Savage, Kienan I., primary, Matchett, Kyle B., primary, Barros, Eliana M., primary, Cooper, Kevin M., primary, Irwin, Gareth W., primary, Gorski, Julia J., primary, Orr, Katy S., primary, Vohhodina, Jekaterina, primary, Kavanagh, Joy N., primary, Madden, Angelina F., primary, Powell, Alexander, primary, Manti, Lorenzo, primary, McDade, Simon S., primary, Park, Ben Ho, primary, Prise, Kevin M., primary, McIntosh, Stuart A., primary, Salto-Tellez, Manuel, primary, Richard, Derek J., primary, Elliott, Christopher T., primary, and Harkin, D. Paul, primary

Published
2023
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14. Supplementary Figures 1-4 from Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

Author

McCabe, Nuala, primary, Hanna, Conor, primary, Walker, Steven M., primary, Gonda, David, primary, Li, Jie, primary, Wikstrom, Katarina, primary, Savage, Kienan I., primary, Butterworth, Karl T., primary, Chen, Clark, primary, Harkin, D. Paul, primary, Prise, Kevin M., primary, and Kennedy, Richard D., primary

Published
2023
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15. Supplementary Methods and Table 1 from Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

Author

McCabe, Nuala, primary, Hanna, Conor, primary, Walker, Steven M., primary, Gonda, David, primary, Li, Jie, primary, Wikstrom, Katarina, primary, Savage, Kienan I., primary, Butterworth, Karl T., primary, Chen, Clark, primary, Harkin, D. Paul, primary, Prise, Kevin M., primary, and Kennedy, Richard D., primary

Published
2023
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16. Data from BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Author

Savage, Kienan I., primary, Matchett, Kyle B., primary, Barros, Eliana M., primary, Cooper, Kevin M., primary, Irwin, Gareth W., primary, Gorski, Julia J., primary, Orr, Katy S., primary, Vohhodina, Jekaterina, primary, Kavanagh, Joy N., primary, Madden, Angelina F., primary, Powell, Alexander, primary, Manti, Lorenzo, primary, McDade, Simon S., primary, Park, Ben Ho, primary, Prise, Kevin M., primary, McIntosh, Stuart A., primary, Salto-Tellez, Manuel, primary, Richard, Derek J., primary, Elliott, Christopher T., primary, and Harkin, D. Paul, primary

Published
2023
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18. Supplementary Figures 1 - 6 from BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Author

Savage, Kienan I., primary, Matchett, Kyle B., primary, Barros, Eliana M., primary, Cooper, Kevin M., primary, Irwin, Gareth W., primary, Gorski, Julia J., primary, Orr, Katy S., primary, Vohhodina, Jekaterina, primary, Kavanagh, Joy N., primary, Madden, Angelina F., primary, Powell, Alexander, primary, Manti, Lorenzo, primary, McDade, Simon S., primary, Park, Ben Ho, primary, Prise, Kevin M., primary, McIntosh, Stuart A., primary, Salto-Tellez, Manuel, primary, Richard, Derek J., primary, Elliott, Christopher T., primary, and Harkin, D. Paul, primary

Published
2023
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19. Supplementary Methods from BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Author

Savage, Kienan I., primary, Matchett, Kyle B., primary, Barros, Eliana M., primary, Cooper, Kevin M., primary, Irwin, Gareth W., primary, Gorski, Julia J., primary, Orr, Katy S., primary, Vohhodina, Jekaterina, primary, Kavanagh, Joy N., primary, Madden, Angelina F., primary, Powell, Alexander, primary, Manti, Lorenzo, primary, McDade, Simon S., primary, Park, Ben Ho, primary, Prise, Kevin M., primary, McIntosh, Stuart A., primary, Salto-Tellez, Manuel, primary, Richard, Derek J., primary, Elliott, Christopher T., primary, and Harkin, D. Paul, primary

Published
2023
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22. Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors

Author

Lappin, Katrina M., primary, Barros, Eliana M., additional, Jhujh, Satpal S., additional, Irwin, Gareth W., additional, McMillan, Hayley, additional, Liberante, Fabio G., additional, Latimer, Cheryl, additional, La Bonte, Melissa J., additional, Mills, Ken I., additional, Harkin, D. Paul, additional, Stewart, Grant S., additional, and Savage, Kienan I., additional

Published
2022
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23. Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer

Author

Parkes, Eileen E, Savage, Kienan I, Lioe, Tong, Boyd, Clinton, Halliday, Sophia, Walker, Steven M, Lowry, Keith, Knight, Laura, Buckley, Niamh E, Grogan, Andrena, Logan, Gemma E, Clayton, Alison, Hurwitz, Jane, Kirk, Stephen J, Xu, Jiamei, Sidi, Fatima Abdullahi, Humphries, Matthew P, Bingham, Victoria, Neo-DDIR Investigators, James, Jaqueline A, James, Colin R, Paul Harkin, D, Kennedy, Richard D, and McIntosh, Stuart A

Abstract

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.

Published
2021

30. Abstract P1-10-17: cGAS-STING driven immune activation predicts response to neoadjuvant chemotherapy and suggests rational IO combination therapies: Results of the Neo-DDIR study

Author

McIntosh, Stuart A, primary, Savage, Kienan I, additional, James, Colin, additional, Lioe, Tong, additional, Walker, Steven, additional, Lowry, Keith, additional, Knight, Laura, additional, McGavigan, Andrena, additional, Logan, Gemma, additional, Hurwitz, Jane, additional, Kirk, Stephen J, additional, Harkin, Paul, additional, Kennedy, Richard D, additional, and Parkes, Eileen E, additional

Published
2020
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31. Multifocal breast cancers are more prevalent inBRCA2versusBRCA1mutation carriers

Author

McCrorie, Alan D, primary, Ashfield, Susannah, additional, Begley, Aislinn, additional, Mcilmunn, Colin, additional, Morrison, Patrick J, additional, Boyd, Clinton, additional, Eccles, Bryony, additional, Greville‐Heygate, Stephanie, additional, Copson, Ellen R, additional, Cutress, Ramsey I, additional, Eccles, Diana M, additional, Savage, Kienan I, additional, and McIntosh, Stuart A, additional

Published
2020
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32. The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export

Author

Vohhodina, Jekaterina, Barros, Eliana M, Savage, Abigail L, Liberante, Fabio G, Manti, Lorenzo, Bankhead, Peter, Cosgrove, Nicola, Madden, Angelina F, Harkin, D Paul, Savage, Kienan I, Vohhodina, Jekaterina, Barros, Eliana M., Savage, Abigail L., Liberante, Fabio G., Manti, Lorenzo, Bankhead, Peter, Cosgrove, Nicola, Madden, Angelina F., Harkin, D Paul, and Savage, Kienan I.

Subjects
Transcription Factor, DNA-Binding Protein, RNA Splicing, Transcription Factors/genetics, Active Transport, Cell Nucleus, Ataxia Telangiectasia Mutated Proteins, Genome Integrity, Repair and Replication, Tumor Suppressor Proteins/genetics, Ataxia Telangiectasia Mutated Protein, SDG 3 - Good Health and Well-being, HEK293 Cell, Ataxia Telangiectasia Mutated Proteins/genetics, Cell Line, Tumor, Genetics, Humans, In Situ Hybridization, Fluorescence, Repressor Proteins/genetics, Tumor Suppressor Protein, Active Transport, Cell Nucleu, Gene Expression Profiling, Tumor Suppressor Proteins, Repressor Protein, DNA-Binding Proteins, Repressor Proteins, HEK293 Cells, Microscopy, Fluorescence, Mutation, RNA Interference, Gene Expression Profiling/methods, DNA-Binding Proteins/genetics, Active Transport, Cell Nucleus/genetics, Human, DNA Damage, Transcription Factors
Abstract

mRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy.

Published
2017

33. Chemoprevention in BRCA1 mutation carriers (CIBRAC): protocol for an open allocation crossover feasibility trial assessing mechanisms of chemoprevention with goserelin and anastrozole versus tamoxifen and acceptability of treatment

Author

Campbell, Aideen M, Morris, Melanie, Gallagher, Rebecca, Boyd, Ruth, Carson, Hazel, Harkin, D Paul, Wielogorska, Ewa, Elliott, Christopher, Savage, Kienan I, and McIntosh, Stuart A

Subjects
SDG 3 - Good Health and Well-being
Abstract

INTRODUCTION: BRCA1 mutation carriers have a significant lifetime risk of breast cancer, with their primary risk-reduction option being bilateral mastectomy. Preclinical work from our laboratory demonstrated that in BRCA1-deficient breast cells, oestrogen and its metabolites are capable of driving DNA damage and subsequent genomic instability, which are well-defined early events in BRCA1-related cancers. Based on this, we hypothesise that a chemopreventive approach which reduces circulating oestrogen levels may reduce DNA damage and genomic instability, thereby providing an alternative to risk-reducing surgery.METHODS AND ANALYSIS: 12 premenopausal women with pathogenic BRCA1 mutations and no previous risk-reducing surgery will be recruited from family history clinics. Participants will be allocated 1:1 to two arms. All will undergo baseline breast biopsies, blood and urine sampling, and quality of life questionnaires. Group A will receive goserelin 3.6 mg/28 days by subcutaneous injection, plus oral anastrozole 1 mg/day, for 12 weeks. Group B will receive oral tamoxifen 20 mg/day for 12 weeks. Following treatment, both groups will provide repeat biopsies, blood and urine samples, and questionnaires. Following a 1-month washout period, the groups will cross over, group A receiving tamoxifen and group B goserelin and anastrozole for a further 12 weeks. After treatment, biopsies, blood and urine samples, and questionnaires will be repeated. DNA damage will be assessed in core biopsies, while blood and urine samples will be used to measure oestrogen metabolite and DNA adduct levels.ETHICS AND DISSEMINATION: This study has ethical approval from the Office for Research Ethics Committees Northern Ireland (16/NI/0055) and the Medicines and Healthcare products Regulatory Agency (MHRA) (reference: 32485/0032/001-0001). The investigational medicinal products used in this trial are licensed and in common use, with well-documented safety information. Dissemination of results will be via high-impact journals and relevant national/international conferences. A copy of the results will be offered to the participants and be made available to patient support groups.TRIAL REGISTRATION NUMBER: EudraCT: 2016-001087-11; Pre-results.

Published
2018

34. ACE: A workbench using evolutionary genetic algorithms for analyzing association in TCGA

Author

Gilmore, Alan R., Alderdice, Matthew, Savage, Kienan I., O'Reilly, Paul G., Roddy, Aideen C., Dunne, Philip D., Lawler, Mark, McDade, Simon S., Waugh, David J., McArt, Darragh G., Gilmore, Alan R., Alderdice, Matthew, Savage, Kienan I., O'Reilly, Paul G., Roddy, Aideen C., Dunne, Philip D., Lawler, Mark, McDade, Simon S., Waugh, David J., and McArt, Darragh G.

Abstract

Modern methods of acquiring molecular data have improved rapidly in recent years, making it easier for researchers to collect large volumes of information. However, this has increased the challenge of recognizing interesting patterns within the data. Atlas Correlation Explorer (ACE) is a user-friendly workbench for seeking associations between attributes in The Cancer Genome Atlas (TCGA) database. It allows any combination of clinical and genomic data streams to be searched using an evolutionary algorithm approach. To showcase ACE, we assessed which RNA sequencing transcripts were associated with estrogen receptor (ESR1) in the TCGA breast cancer cohort. The analysis revealed already well-established associations with XBP1 and FOXA1, but also identified a strong association with CT62, a potential immunotherapeutic target with few previous associations with breast cancer. In conclusion, ACE can produce results for very large searches in a short time and will serve as an increasingly useful tool for biomarker discovery in the big data era. Significance: ACE uses an evolutionary algorithm approach to perform large searches for associations between any combinations of data in the TCGA database.

Published
2019

37. Multifocal breast cancers are more prevalent inBRCA2versusBRCA1mutation carriers

Author

McCrorie, Alan D, primary, Ashfield, Susannah, additional, Begley, Aislinn, additional, Mcilmunn, Colin, additional, Morrison, Patrick J., additional, Boyd, Clinton, additional, Eccles, Bryony, additional, Greville-Heygate, Stephanie, additional, Copson, Ellen R, additional, Cutress, Ramsey I., additional, Eccles, Diana M, additional, Savage, Kienan I., additional, and McIntosh, Stuart A, additional

Published
2019
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40. Chemoprevention in BRCA1 mutation carriers (CIBRAC): protocol for an open allocation crossover feasibility trial assessing mechanisms of chemoprevention with goserelin and anastrozole versus tamoxifen and acceptability of treatment

Author

Campbell, Aideen M, primary, Morris, Melanie, additional, Gallagher, Rebecca, additional, Boyd, Ruth, additional, Carson, Hazel, additional, Harkin, D Paul, additional, Wielogorska, Ewa, additional, Elliott, Christopher, additional, Savage, Kienan I, additional, and McIntosh, Stuart A, additional

Published
2018
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42. Multifocal breast cancers are more prevalent in BRCA2 versus BRCA1 mutation carriers.

Author

McCrorie, Alan D, Ashfield, Susannah, Begley, Aislinn, Mcilmunn, Colin, Morrison, Patrick J, Boyd, Clinton, Eccles, Bryony, Greville‐Heygate, Stephanie, Copson, Ellen R, Cutress, Ramsey I, Eccles, Diana M, Savage, Kienan I, and McIntosh, Stuart A

Subjects
BREAST cancer, BREAST surgery, ODDS ratio, CROSS-sectional method
Abstract

Multifocal (MF)/multicentric (MC) breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ~10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort of BRCA1/2 mutation carriers with breast cancer from Northern Ireland via cross‐sectional analysis. Data from 211 women with BRCA1/2 mutations (BRCA1‐91, BRCA2‐120) and breast cancer were collected including age, tumour focality, size, type, grade and receptor profile. The prevalence of multifocality/multicentricity within this group was 25% but, within subgroups, prevalence amongst BRCA2 carriers was more than double that of BRCA1 carriers (p = 0.001). Women affected by MF/MC tumours had proportionately higher oestrogen receptor positivity (p = 0.001) and lower triple negativity (p = 0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. The odds of a BRCA2 carrier developing MF/MC cancer were almost four‐fold higher than a BRCA1 carrier (odds ratio: 3.71, CI: 1.77–7.78, p = 0.001). These findings were subsequently validated in a second, large independent cohort of patients with BRCA‐associated breast cancers from a UK‐wide multicentre study. This confirmed a significantly higher prevalence of MF/MC tumours amongst BRCA2 mutation carriers compared with BRCA1 mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2‐associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision‐making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients. [ABSTRACT FROM AUTHOR]

Published
2020
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49. Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Author

Parkes, Eileen E., primary, Walker, Steven M., additional, Taggart, Laura E., additional, McCabe, Nuala, additional, Knight, Laura A., additional, Wilkinson, Richard, additional, McCloskey, Karen D., additional, Buckley, Niamh E., additional, Savage, Kienan I., additional, Salto-Tellez, Manuel, additional, McQuaid, Stephen, additional, Harte, Mary T., additional, Mullan, Paul B., additional, Harkin, D. Paul, additional, and Kennedy, Richard D., additional

Published
2016
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50. Abstract 4000: A DNA damage response deficiency (DDRD) group in breast cancer is associated with activation of the STING innate immune pathway and PD-L1 expression

Author

Parkes, Eileen E., primary, Walker, Steven M., additional, McCabe, Nuala, additional, Taggart, Laura E., additional, Hill, Laura, additional, Buckley, Niamh E., additional, Savage, Kienan I., additional, Salto-Tellez, Manuel, additional, McQuaid, Stephen, additional, Harte, Mary T., additional, Mullan, Paul B., additional, Harkin, D Paul, additional, and Kennedy, Richard D., additional

Published
2016
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