Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repa...
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| Format: | Article |
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American Association for Cancer Research
2017
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| Online Access: | https://eprints.nottingham.ac.uk/43070/ |
| _version_ | 1848796632633573376 |
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| author | Green, Andrew R. Aleskandarany, Mohammed A. Ali, Reem Hodgson, Eleanor Grace Atabani, Suha De Souza, Karen Ellis, Ian O. Rakha, Emad Madhusudan, Srinivasan |
| author_facet | Green, Andrew R. Aleskandarany, Mohammed A. Ali, Reem Hodgson, Eleanor Grace Atabani, Suha De Souza, Karen Ellis, Ian O. Rakha, Emad Madhusudan, Srinivasan |
| author_sort | Green, Andrew R. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor-negative (ER-) cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+ tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER- cells, and poor survival (all P ≤ 0.01). PD-1+ or PD-L1+ breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER- (all with P values ≤ 0.01), and poor survival (P = 0.00021 and P = 0.00022, for PD-1+ and PD-L1+ cancers, respectively) including in an independent ER- validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer. |
| first_indexed | 2025-11-14T19:51:04Z |
| format | Article |
| id | nottingham-43070 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:51:04Z |
| publishDate | 2017 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-430702020-05-04T18:40:13Z https://eprints.nottingham.ac.uk/43070/ Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers Green, Andrew R. Aleskandarany, Mohammed A. Ali, Reem Hodgson, Eleanor Grace Atabani, Suha De Souza, Karen Ellis, Ian O. Rakha, Emad Madhusudan, Srinivasan Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor-negative (ER-) cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+ tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER- cells, and poor survival (all P ≤ 0.01). PD-1+ or PD-L1+ breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER- (all with P values ≤ 0.01), and poor survival (P = 0.00021 and P = 0.00022, for PD-1+ and PD-L1+ cancers, respectively) including in an independent ER- validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer. American Association for Cancer Research 2017-04-01 Article PeerReviewed Green, Andrew R., Aleskandarany, Mohammed A., Ali, Reem, Hodgson, Eleanor Grace, Atabani, Suha, De Souza, Karen, Ellis, Ian O., Rakha, Emad and Madhusudan, Srinivasan (2017) Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers. Cancer Immunology Research, 5 (4). pp. 292-299. ISSN 2326-6074 http://cancerimmunolres.aacrjournals.org/content/5/4/292.long doi:10.1158/2326-6066.CIR-16-0195 doi:10.1158/2326-6066.CIR-16-0195 |
| spellingShingle | Green, Andrew R. Aleskandarany, Mohammed A. Ali, Reem Hodgson, Eleanor Grace Atabani, Suha De Souza, Karen Ellis, Ian O. Rakha, Emad Madhusudan, Srinivasan Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title | Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title_full | Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title_fullStr | Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title_full_unstemmed | Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title_short | Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers |
| title_sort | clinical impact of tumor dna repair expression and t-cell infiltration in breast cancers |
| url | https://eprints.nottingham.ac.uk/43070/ https://eprints.nottingham.ac.uk/43070/ https://eprints.nottingham.ac.uk/43070/ |