Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers
| Autor: | Rajesh Gottimukkala, Kathy D. Miller, Rutuja Atale, Mufti N. Ahmad, Jeffrey P. Solzak, Bryan P. Schneider, David C. Wedge, Yu-Hsiang Chen, Dumitru Brinza, James Veitch, Walt Short, Mircea Ivan, Milan Radovich, Charles Scafe, Sunil Badve, Bradley A. Hancock, Xiongbin Lu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Neoplasm
Residual Somatic cell Triple Negative Breast Neoplasms Kaplan-Meier Estimate MYC Somatic evolution in cancer SMAD2 Lymphocytic Infiltrate 0302 clinical medicine Surgical oncology Recurrence Antineoplastic Combined Chemotherapy Protocols TP53 TGF-beta Breast Relapse Cancer Manchester Cancer Research Centre High-Throughput Nucleotide Sequencing Genomics Prognosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neoadjuvant Therapy Gene Expression Regulation Neoplastic Treatment Outcome 030220 oncology & carcinogenesis Neoplastic Stem Cells Female Chemoresistance Signal Transduction Research Article DNA Copy Number Variations Biology lcsh:RC254-282 03 medical and health sciences Breast cancer Germline mutation medicine Biomarkers Tumor Humans Gene ResearchInstitutes_Networks_Beacons/mcrc Point mutation medicine.disease Drug Resistance Neoplasm Mutation Cancer research Triple-negative Neoplasm Recurrence Local Tumor Suppressor Protein p53 |
| Zdroj: | Breast Cancer Research, Vol 21, Iss 1, Pp 1-15 (2019) Breast Cancer Research : BCR Hancock, B A, Chen, Y-H, Solzak, J P, Ahmad, M N, Wedge, D C, Brinza, D, Scafe, C, Veitch, J, Gottimukkala, R, Short, W, Atale, R V, Ivan, M, Badve, S S, Schneider, B P, Lu, X, Miller, K D & Radovich, M 2019, ' Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers ', Breast Cancer Research . https://doi.org/10.1186/s13058-019-1171-7 |
| DOI: | 10.1186/s13058-019-1171-7 |
| Popis: | Background Approximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development. Methods We assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes. Results Analysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2. Conclusions We conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation. Electronic supplementary material The online version of this article (10.1186/s13058-019-1171-7) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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