Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors
Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patient...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Breast Cancer Research |
| Online Access: | https://doi.org/10.1186/s13058-023-01656-x |
| _version_ | 1797817693353541632 |
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| author | Xiaojia Tang Kevin J. Thompson Krishna R. Kalari Jason P. Sinnwell Vera J. Suman Peter T. Vedell Sarah A. McLaughlin Donald W. Northfelt Alvaro Moreno Aspitia Richard J. Gray Jodi M. Carter Richard Weinshilboum Liewei Wang Judy C. Boughey Matthew P. Goetz |
| author_facet | Xiaojia Tang Kevin J. Thompson Krishna R. Kalari Jason P. Sinnwell Vera J. Suman Peter T. Vedell Sarah A. McLaughlin Donald W. Northfelt Alvaro Moreno Aspitia Richard J. Gray Jodi M. Carter Richard Weinshilboum Liewei Wang Judy C. Boughey Matthew P. Goetz |
| author_sort | Xiaojia Tang |
| collection | DOAJ |
| description | Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patients who do not achieve a pathological complete response (pCR). Based on this premise, we hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence. Methods and results We investigated 24 samples from 12 non-LAR TNBC patients with paired pre- and post-NAC data, including four patients with recurrence shortly after surgery (< 24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and nonrecurrent TNBC tumors; however, post-NAC samples demonstrated significant alterations in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the 9 paired non-LAR samples available in the NAC I-SPY1 trial confirmed 56 gene sets. Within these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n = 392) breast cancer dataset with relapse-free survival (RFS) data was used to refine our gene list to a 17-gene signature. A threefold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine-learning models. Due to the limited number of studies with pre- and post-NAC TNBC tumor data, further validation of the signature is needed. Conclusion Analysis of multiomics data from post-NAC TNBC chemoresistant tumors showed down regulation of mismatch repair and tubulin pathways. Additionally, we identified a 17-gene signature in TNBC associated with post-NAC recurrence enriched with down-regulated immune genes. |
| first_indexed | 2024-03-13T08:57:12Z |
| format | Article |
| id | doaj.art-3af3f74d177a4754a631cf8c8eef5d57 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-03-13T08:57:12Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-3af3f74d177a4754a631cf8c8eef5d572023-05-28T11:31:27ZengBMCBreast Cancer Research1465-542X2023-05-0125111810.1186/s13058-023-01656-xIntegration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumorsXiaojia Tang0Kevin J. Thompson1Krishna R. Kalari2Jason P. Sinnwell3Vera J. Suman4Peter T. Vedell5Sarah A. McLaughlin6Donald W. Northfelt7Alvaro Moreno Aspitia8Richard J. Gray9Jodi M. Carter10Richard Weinshilboum11Liewei Wang12Judy C. Boughey13Matthew P. Goetz14Department of Quantitative Health Sciences, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Quantitative Health Sciences, Mayo ClinicDepartment of Surgery, Mayo ClinicDepartment of Medical Oncology, Mayo ClinicDepartment of Medical Oncology, Mayo ClinicDepartment of Surgery, Mayo ClinicDepartment of Pathology, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Surgery, Mayo ClinicDepartment of Medical Oncology, Mayo ClinicAbstract Background Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patients who do not achieve a pathological complete response (pCR). Based on this premise, we hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence. Methods and results We investigated 24 samples from 12 non-LAR TNBC patients with paired pre- and post-NAC data, including four patients with recurrence shortly after surgery (< 24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and nonrecurrent TNBC tumors; however, post-NAC samples demonstrated significant alterations in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the 9 paired non-LAR samples available in the NAC I-SPY1 trial confirmed 56 gene sets. Within these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n = 392) breast cancer dataset with relapse-free survival (RFS) data was used to refine our gene list to a 17-gene signature. A threefold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine-learning models. Due to the limited number of studies with pre- and post-NAC TNBC tumor data, further validation of the signature is needed. Conclusion Analysis of multiomics data from post-NAC TNBC chemoresistant tumors showed down regulation of mismatch repair and tubulin pathways. Additionally, we identified a 17-gene signature in TNBC associated with post-NAC recurrence enriched with down-regulated immune genes.https://doi.org/10.1186/s13058-023-01656-x |
| spellingShingle | Xiaojia Tang Kevin J. Thompson Krishna R. Kalari Jason P. Sinnwell Vera J. Suman Peter T. Vedell Sarah A. McLaughlin Donald W. Northfelt Alvaro Moreno Aspitia Richard J. Gray Jodi M. Carter Richard Weinshilboum Liewei Wang Judy C. Boughey Matthew P. Goetz Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors Breast Cancer Research |
| title | Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors |
| title_full | Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors |
| title_fullStr | Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors |
| title_full_unstemmed | Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors |
| title_short | Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors |
| title_sort | integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple negative chemotherapy resistant breast tumors |
| url | https://doi.org/10.1186/s13058-023-01656-x |
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