scholarly journals Genome Instability-Derived Genes Are Novel Prognostic Biomarkers for Triple-Negative Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Maoni Guo ◽  
San Ming Wang
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Genome Instability ◽  
Molecular Taxonomy ◽  
Gene Signature ◽  
Rank Test ◽  
Log Rank Test ◽  
A Genome

BackgroundTriple-negative breast cancer (TNBC) is an aggressive disease. Recent studies have identified genome instability-derived genes for patient outcomes. However, most of the studies mainly focused on only one or a few genome instability-related genes. Prognostic potential and clinical significance of genome instability-associated genes in TNBC have not been well explored.MethodsIn this study, we developed a computational approach to identify TNBC prognostic signature. It consisted of (1) using somatic mutations and copy number variations (CNVs) in TNBC to build a binary matrix and identifying the top and bottom 25% mutated samples, (2) comparing the gene expression between the top and bottom 25% samples to identify genome instability-related genes, and (3) performing univariate Cox proportional hazards regression analysis to identify survival-associated gene signature, and Kaplan–Meier, log-rank test, and multivariate Cox regression analyses to obtain overall survival (OS) information for TNBC outcome prediction.ResultsFrom the identified 111 genome instability-related genes, we extracted a genome instability-derived gene signature (GIGenSig) of 11 genes. Through survival analysis, we were able to classify TNBC cases into high- and low-risk groups by the signature in the training dataset (log-rank test p = 2.66e−04), validated its prognostic performance in the testing (log-rank test p = 2.45e−02) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (log-rank test p = 2.57e−05) datasets, and further validated the predictive power of the signature in five independent datasets.ConclusionThe identified novel signature provides a better understanding of genome instability in TNBC and can be applied as prognostic markers for clinical TNBC management.

scholarly journals A Novel Immune Checkpoint-Related Gene Signature to Predict Overall Survival and Immunotherapy Response in Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Jingyi Liu ◽  
Siyuan Tian ◽  
Yuwei Ling ◽  
Xinyi Zhang ◽  
Yan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Cox Regression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Molecular Taxonomy ◽  
Gene Signature ◽  
Cox Regression Analysis

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective therapeutic targets. Immunotherapy is considered as a novel treatment strategy for TNBC. However, only some patients could benefit from the treatment. Limited studies have comprehensively explored expression patterns and prognostic value of immune checkpoint genes (ICGs) in TNBC. In this study, we downloaded relevant ICGs expression profiles and clinical TNBC data from the Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was employed to develop a multi-gene signature for predicting the prognostic outcome. PDCD1, PDCD1LG2 and KIR3DL2 were identified as hub genes and incorporated into the model. This gene signature could stratify patients into two prognostic subgroups, and unfavorable clinical outcomes were observed in high-risk patients. The predictive performance was assessed by the receiver operating characteristic curves. Moreover, we also analyzed differences in immune status and therapeutic response between both groups. This novel gene signature may be served as a robust prognostic marker, but also an indicator reflecting immunotherapy response.

scholarly journals A Novel Platelet-Related Gene Signature for Predicting the Prognosis of Triple-Negative Breast Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Jindong Xie ◽  
Yutian Zou ◽  
Feng Ye ◽  
Wanzhen Zhao ◽  
Xinhua Xie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Risk Group ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Clinical Prognosis

Regarded as the most invasive subtype, triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) proteins. Platelets have recently been shown to be associated with metastasis of malignant tumors. Nevertheless, the status of platelet-related genes in TNBC and their correlation with patient prognosis remain unknown. In this study, the expression and variation levels of platelet-related genes were identified and patients with TNBC were divided into three subtypes. We collected cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, we constructed a seven-gene signature which classified the two cohorts of patients with TNBC into low- or high-risk groups. Patients in the high-risk group were more likely to have lower survival rates than those in the low-risk group. The risk score, incorporated with the clinical features, was confirmed as an independent factor for predicting the overall survival (OS) time. Functional enrichment analyses revealed the involvement of a variety of vital biological processes and classical cancer-related pathways that could be important to the ultimate prognosis of TNBC. We then built a nomogram that performed well. Moreover, we tested the model in other cohorts and obtained positive outcomes. In conclusion, platelet-related genes were closely related to TNBC, and this novel signature could serve as a tool for the assessment of clinical prognosis.

scholarly journals Androgen Receptor Highjacks ErbB-2 Nuclear Function to Induce Triple Negative Breast Cancer Growth

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A804-A804
Author(s):  
Agustina Roldán Deamicis ◽  
Robert H Oakley ◽  
Sergio Andonegui Helguera ◽  
Mariela B Lenze ◽  
Santiago Madera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Nuclear Migration ◽  
Subcellular Fractionation ◽  
Gene Signature ◽  
Dominant Negative ◽  
Cox Regression Analysis

Abstract Triple negative breast cancer (TNBC) has poor prognosis and neither established biomarkers nor therapeutic targets. On the one hand the androgen receptor (AR), a steroid hormone receptor (SR) which is expressed in 10-53% of TNBC and proved to be critical for BC proliferation, has been proposed as a new target in TNBC. On the other hand, we and others have shown that membrane ErbB-2 migrates to the nucleus (nuclear ErbB-2, NErbB-2) where it binds DNA at HER-2 associated sequences (HAS) to regulate BC proliferation and migration. Since we have previously shown a functional interplay between growth factors and SR signaling pathways in BC, we propose the existence of an interaction between AR and ErbB-2 which is involved in NErbB-2+/AR+ BC growth. The experimental model used was the human TNBC cell line MDA-MB-453 which displays high expression levels of AR and NErbB-2. By Western Blot (WB) we found that dihydrotestosterone (DHT) treatment for short times (minutes) did not regulate ErbB-2 phosphorylation status at residues Tyr1221/1222 and 1248 which were constitutively activated. However, DHT led to an increase in ErbB-2 phosphorylation at residue Tyr877 which we have proved to be required for ErbB-2 nuclear migration. The latter effect was blocked by the AR antagonist enzalutamide (enza). Blockage of Src activity with dasatinib inhibited DHT-induced ErbB-2 phosphorylation at Tyr877. By Immunofluorescence and confocal microscopy analyses and subcellular fractionation studies we demonstrated that DHT induced ErbB-2 nuclear migration which was inhibited by enza. By chIP we found that DHT induced ErbB-2 recruitment to a HAS site in ERK5, a gene involved in BC proliferation, and to a HAS site in FKBP5, a classical AR responsive gene. By WB we demonstrated that transfection with an ErbB-2 mutant which is unable to translocate to the nucleus and functions as a dominant negative inhibitor of ErbB-2 nuclear migration (hErbB-2ΔNLS), inhibited FKBP51 up-regulation by DHT. Finally, by microarray and bioinformatics analysis we identified 315 differentially expressed genes (DEGs) in the presence of DHT and NErbB-2 eviction. Enrichment analyses showed that the DEGs belonged to the immune response and interferon pathways. Kaplan-Meier analysis revealed that the expression of 6 genes was significantly associated with overall survival in TNBC patients from the METABRIC cohort: CXCL10, TAP1, STAT1, NMI, HLA-A and NLRC5. Multivariate Cox regression analysis identified the combined expression of the 6 genes as an independent predictor of better clinical outcome in TNBC (HR: 0.56, 95% CI 0.38-0.82, P = 0.003). In conclusion, our findings evidence that DHT-activated AR induces Src-mediated ErbB-2 rapid activation and its migration to the nucleus where it binds to HAS sites in the DNA. Moreover, based on the DEGs of NErbB-2 eviction in presence of DHT we identified a gene signature associated with favorable outcome in TNBC.

Effect of incorporation of cisplatin to adjuvant chemotherapy for triple-negative breast cancer patients of unknown BRCA mutation status on survival.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12009-e12009
Author(s):  
Chia-Yen Hung ◽  
Ying-Wen Su ◽  
Ruey Kuen Hsieh ◽  
Hung-Bun Lam ◽  
Yuan-Ching Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Stage I ◽  
Stage Ii ◽  
Rank Test ◽  
Mutation Status ◽  
Log Rank Test ◽  
The Mean

e12009 Background: Recently, adding platinum to neoadjuvant chemotherapy (C/T) was associated with improved response rate in early Triple-negative breast cancer (TNBC). Whether incorporation of platinum to adjuvant C/T was associated clinical benefit has not been well investigated. Methods: Patients with resected TNBC who had available staging information and complete treatment at Mackay Memorial Hospital between 2004 and 2010 were enrolled for retrieving cllinical and pathologic information. Patients were monitored until death or Jan 2015. Statistical analysis was performed to determine the association of cancer-related overall survival (OS) and clinicopathological features. For stage I/II patients, 18 out of 115 received cisplatin-containing C/T. The mean OS for stage I/II patients with and without cisplatin-containing C/T was 6.05 years (standard error [SE]: 0.72 ) and 9.55 years (SE: 0.31), respectively ( P=0.07; log-rank test). For stage II/III patients, 20 out of 81 received cisplatin-containing C/T. The mean OS for stage II/III patients with and without cisplatin-containing C/T was 6.51 years (SE: 0.64) and 8.65 years (SE: 0.38), respectively ( P=0.56; log-rank test). In multivariate analysis for stage I-III patients, only age was significantly associated with OS (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.00-1.10). The adjusted HR for adding cisplatin to adjuvant C/T was 2.17 (95% CI: 0.729-6.44). Conclusions: In this small-numbered retrospective study, adding cisplatin to adjuvant C/T for TNBC with unknown BRCA mutation status did not have OS benefit. [Table: see text]

scholarly journals Neutrophil-to-lymphocyte ratio predicts early mortality in females with metastatic triple-negative breast cancer

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243447
Author(s):  
Gabriel de la Cruz-Ku ◽  
Diego Chambergo-Michilot ◽  
J. Smith Torres-Roman ◽  
Pamela Rebaza ◽  
Joseph Pinto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Mortality ◽  
Neutrophil To Lymphocyte Ratio ◽  
Sensitivity Analyses ◽  
Rank Test ◽  
Poor Overall Survival ◽  
Lymphocyte Ratio

Background The aim of this study was to determine the utility of the neutrophil-to-lymphocyte ratio (NLR) as a biomarker for predicting early-mortality (<2 years) among females with metastatic triple-negative breast cancer (mTNBC). Methods We reviewed 118 medical records of females with mTNBC. The cut-off value for the NLR (<2.5 and ≥2.5) was determined with receiver operating characteristic curves (area under the curve: 0.73; 95% CI: 0.62–0.85). Survival curves were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression was used to identify the risk of mortality at two years. Moreover, we performed sensitivity analyses with different cut-off values and a subgroup analysis in females that only received chemotherapy. Results The median follow-up was 24 months. Females with NLR ≥2.5 had a poor overall survival compared to females with NLR <2.5 (6% vs. 28%, p<0.001) at two years. This outcome remained when we stratified for females that only received chemotherapy (8% vs. 36%, p = 0.001). Multivariate analyses identified NLR ≥2.5 as a poor prognostic risk factor for mortality in the entire population (HR: 2.12, 95% CI: 1.32–3.39) and among females that received chemotherapy (HR: 2.68, 95% CI: 1.46–4.92). Conclusion The NLR is an accessible and reliable biomarker that predicts early mortality among females with mTNBC. Our results suggest that females with high NLR values have poor prognosis despite receiving standard chemotherapy. Health providers should evaluate the possibility to enroll these patients in novel immunotherapy trials.

Triple-negative breast cancer survival in women age 75 and older.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1060-1060
Author(s):  
Judith April Malmgren ◽  
Henry G. Kaplan ◽  
Mary K. Atwood
Keyword(s):  
Breast Cancer ◽  
Older Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Rank Test ◽  
Disease Specific Survival ◽  
Younger Women ◽  
Log Rank Test ◽  
Disease Specific

1060 Background: Triple-negative breast cancer (TNBC) is associated with a high recurrence rate and poor prognosis, despite high initial response to chemotherapy. It is not known if TNBC patients 75 years older, an age group less likely to be treated with adjuvant chemotherapy, have the same mortality risk as younger women. Methods: We conducted a prospective cohort study of all women presenting with primary TNBC, age 21-89, stage I-III from 1998-2009 identified and tracked by our registry (n=529). Clinical characteristics were chart abstracted at diagnosis and follow up. The Kaplan-Meier method and log rank test were used for disease specific survival (DSS) and overall survival (OS) by age. Results: Mean follow up was 6.6 years, range 1.98-13.41 years. Distribution by age was 92% <75 years (n = 485) and 8% 75+ years (n = 44). The two age groups did not differ by histologic or nuclear grade, stage, or radiation therapy receipt (age 75+ by stage: I = 46%, II = 34%, III 21%, age <75: I = 37%, II = 46%, III = 17% [not significant]). Patients 75 and older were less likely to be treated with adjuvant chemotherapy (32% vs. 91%, Pearson chi square test = 119.32, p <.001). 5 year DSS was not significantly different for patients age <75 years compared to patients age 75+ years (85% vs. 84%). However, 5 year OS was significantly worse for 75 year and older patients (65%) compared to <75 year old patients (83%) (log rank test = 13.97, p < .001). Conclusions: In our institutional cohort, triple-negative breast cancer in older women had similar prognostic indicators (stage and histologic grade) compared to younger women and older women had equivalent disease specific survival in spite of substantially less chemotherapy treatment. At 5 years post diagnosis, women 75 years and older were 18% more likely to die of causes other than breast cancer.

scholarly journals Neutrophil-to-lymphocyte ratio as a predictor of early death in metastatic triple-negative breast cancer

2020 ◽  
Author(s):  
Gabriel De la Cruz-Ku ◽  
Diego Chambergo-Michilot ◽  
J. Smith Torres-Roman ◽  
Pamela Rebaza ◽  
Joseph Pinto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Care Center ◽  
Tertiary Care ◽  
Metastatic Breast ◽  
Early Death ◽  
Sensitivity Analyses ◽  
Rank Test

Abstract Background The prediction of survival using the neutrophil-to-lymphocytes ratio (NLR) in metastatic breast cancer is still under debate. We aimed to determine the mortality prognostic value of the NLR in female patients with metastatic triple-negative breast cancer. Methods. We reviewed 118 medical records of patients diagnosed and treated in a tertiary-care center over a 14-year period. The cut-off value for the NLR (<2.5 and ≥2.5) was determined with receiver operating characteristic curves (area under the curve: 0.73; 95% CI: 0.615, 0.851). Survival curves were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression was used to identify the risk of mortality at two years. We further performed sensitivity analyses with different cut-off values and subgroup analysis in patients that only received chemotherapy. Results. The median follow-up was 24 months. Patients with an NLR ≥2.5 had a worse overall survival compared to patients with a NLR <2.5 (6% vs. 28%, p<0.001) at two years. This outcome remained consistent when we stratified for patients that received chemotherapy (8% vs. 36%, p=0.001). Multivariate analysis identified the NLR (≥2.5 vs. <2.5) at diagnosis as a prognostic risk factor for mortality in the entire population (HR: 2.12, 95% CI: 1.32-3.39) and in patients that received chemotherapy (HR: 2.68, 95% CI: 1.46 – 4.92). Conclusions. The NLR is an accessible biomarker that predicts early mortality in patients with metastatic triple-negative breast cancer. Physicians can use these results to predict survival in these patients.

A novel three-long noncoding RNA risk score system for the prognostic prediction of triple-negative breast cancer

2021 ◽  
Vol 15 (1) ◽  
pp. 43-55
Author(s):  
Chao Yuan ◽  
Hongjun Yuan ◽  
Li Chen ◽  
Miaomiao Sheng ◽  
Wenru Tang
Keyword(s):  
Breast Cancer ◽  
Risk Score ◽  
Triple Negative Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Triple Negative ◽  
Cox Regression ◽  
Characteristic Curve ◽  
Gene Expression Omnibus ◽  
Prognostic Prediction

Background: Triple-negative breast cancer (TNBC) is characterized by fast tumor increase, rapid recurrence and natural metastasis. We aimed to identify a genetic signature for predicting the prognosis of TNBC. Materials & methods: We conducted a weighted correlation network analysis of datasets from the Gene Expression Omnibus. Multivariate Cox regression was used to construct a risk score model. Results: The multi-factor risk scoring model was meaningfully associated with the prognosis of patients with TBNC. The predictive power of the model was demonstrated by the time-dependent receiver operating characteristic curve and Kaplan–Meier curve, and verified using a validation set. Conclusion: We established a long noncoding RNA-based model for the prognostic prediction of TNBC.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

scholarly journals Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5590
Author(s):  
Alyssa Vito ◽  
Nader El-Sayes ◽  
Omar Salem ◽  
Yonghong Wan ◽  
Karen L. Mossman
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Macrophage Polarization ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Differential Gene ◽  
Microarray Analyses ◽  
Tumor Cell Killing

The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

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