No common denominator for breast cancer lymph node metastasis.
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ABSTRACT:
SUBMITTER: Weigelt B
PROVIDER: S-EPMC2361648 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Single cancer cell-sequencing studies currently use randomly selected cells, limiting correlations among genomic aberrations, morphology, and spatial localization. We laser-captured microdissected single cells from morphologically distinct areas of primary breast cancer and corresponding lymph node metastasis and performed whole-exome or deep-target sequencing of more than 100 such cells. Two major subclones coexisted in different areas of the primary tumor, and the lymph node metastasis originated from a minor subclone in the invasive front of the primary tumor, with additional copy number changes, including chr8q gain, but no additional point mutations in driver genes. Lack of metastasis-specific driver events led us to assess whether other clonal and subclonal genomic aberrations preexisting in primary tumors contribute to lymph node metastasis. Gene mutations and copy number variations analyzed in 5 breast cancer tissue sample sets revealed that copy number variations in several genomic regions, including areas within chr1p, chr8q, chr9p, chr12q, and chr20q, harboring several metastasis-associated genes, were consistently associated with lymph node metastasis. Moreover, clonal expansion was observed in an area of morphologically normal breast epithelia, likely driven by a driver mutation and a subsequent amplification in chr1q. Our study illuminates the molecular evolution of breast cancer and genomic aberrations contributing to metastases.
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Project description:Early detection and discovery of new therapeutic targets are urgently needed to improve the breast cancer treatment outcome. Here we conducted an official clinical trial with cross-validation to corroborate human plasma Hsp90α as a novel breast cancer biomarker. Importantly, similar results were noticed in detecting early-stage breast cancer patients. Additionally, levels of plasma Hsp90α in breast cancer patients were gradually elevated as their clinical stages of regional lymph nodes advanced. In orthotopic breast cancer mouse models, administrating with recombinant Hsp90α protein increased both the primary tumor lymphatic vessel density and sentinel lymph node metastasis by 2 and 10 times, respectively. What is more, Hsp90α neutralizing antibody treatment approximately reduced 70% of lymphatic vessel density and 90% of sentinel lymph node metastasis. In the in vitro study, we demonstrated the role of extracellular Hsp90α (eHsp90α) as a pro-lymphangiogenic factor, which significantly enhanced migration and tube formation abilities of lymphatic endothelial cells (LECs). Mechanistically, eHsp90α signaled to the AKT pathway through low-density lipoprotein receptor-related protein 1 (LRP1) to upregulate the expression and secretion of CXCL8 in the lymphangiogenic process. Collectively, this study proves that plasma Hsp90α serves as an auxiliary diagnosis biomarker and eHsp90α as a molecular mediator promoting lymphangiogenesis in breast cancer.
| S-EPMC8305043 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and no targeted treatments. TNBC patients are more likely to develop metastases and relapse than patients with other breast cancer subtypes. We aimed to identify TNBC-specific genes and genes associated with lymph node metastasis, one of the first signs of metastatic spread. A total of 33 TNBCs were used; 17 of which had matched normal adjacent tissues available, and 15 with matched lymph node metastases. Gene expression microarray analysis was used to reveal genes that were differentially expressed between these groups. We identified and validated 66 genes that are significantly altered when comparing tumours to normal adjacent samples. Further, we identified 83 genes that are associated with lymph node metastasis and correlated these with miRNA-expression. Pathway analysis revealed their involvement in DNA repair, recombination and cell death, chromosomal instability and other known cancer-related pathways. Finally, four genes were identified that were specific for TNBC, of which one was associated with overall survival. This study has identified novel genes involved in LN metastases in TNBC and genes that are TNBC specific that may be used as treatment targets or prognostic indicators in the future.
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Project description:Background: Circular RNAs (circRNAs) have been shown to play important roles in the development and progression of human cancers. Emerging evidence shows that circRNAs have the potential to be promising biomarkers for cancer diagnosis and prognosis. However, the roles of circRNAs in breast cancer axillary lymph node metastasis (ALNM) remain to be determined. Methods: Transcriptome sequencing was utilized to screen the differentially expressed circRNAs in three breast cancer tissues with ALNM and three without ALNM. Differentially expressed circRNAs were further verified by quantitative real-time PCR. Moreover, receiver operating characteristic (ROC) curve analysis was performed to calculate the value of circRNAs to distinguish breast cancer tissues with ALNM and those without ALNM. To explore the potential mechanism of the circRNAs, a circRNA-miRNA-mRNA network was constructed based on the CircInteractome, circBank, and mirDIP online software. Results: In total, 31 differentially expressed circRNAs were identified by transcriptome sequencing; among them, 21 were upregulated and 10 were downregulated in breast cancer with ALNM compared to those without ALNM. Circ_0000160 was validated to be downregulated in breast cancer tissues with ALNM compared with those without ALNM. The ROC curve showed the ability of circ_0000160 to distinguish breast cancer tissues with ALNM and those without ALNM, with an area under the curve of 0.7435. Furthermore, bioinformatics analysis revealed that the predicted mRNAs for circ_0000160 may be related to lymph node metastasis. The predicted mRNAs for circ_0000160 may be involved in many cancer-related pathways. Conclusion: A decreased expression of circ_0000160 was found in breast cancer with axillary lymph node metastasis. Circ_0000160 may have the potential to distinguish breast cancer with axillary lymph node metastasis from those without axillary lymph node metastasis.
| S-EPMC8861307 | biostudies-literature
Project description:ObjectivesTo determine whether ultrasound radiomics can be used to distinguish axillary lymph nodes (ALN) metastases in breast cancer based on ALN imaging.MethodsA total of 147 breast cancer patients with 41 non-metastatic lymph nodes and 109 metastatic lymph nodes were divided into a training set (105 ALN) and a validation set (45 ALN). Radiomics features were extracted from ultrasound images and a radiomics signature (RS) was built. The Intraclass correlation coefficients (ICCs), Spearman correlation analysis, and least absolute shrinkage and selection operator (LASSO) methods were used to select the ALN status-related features. All images were assessed by two radiologists with at least 10 years of experience in ALN ultrasound examination. The performance levels of the model and radiologists in the training and validation subgroups were then evaluated and compared.ResultRadiomics signature accurately predicted the ALN status, achieved an area under the receiver operator characteristic curve of 0.929 (95%CI, 0.881-0.978) and area under curve(AUC) of 0.919 (95%CI, 95%CI, 0.841-0.997) in training and validation cohorts respectively. The radiomics model performed better than two experts' prediction of ALN status in both cohorts (P<0.05). Besides, prediction in subgroups based on baseline clinicopathological information also achieved good discrimination performance, with an AUC of 0.937, 0.918, 0.885, 0.930, and 0.913 in HR+/HER2-, HER2+, triple-negative, tumor sized ≤ 3cm and tumor sized>3 cm, respectively.ConclusionThe radiomics model demonstrated a good ability to predict ALN status in patients with breast cancer, which might provide essential information for decision-making.
| S-EPMC10641324 | biostudies-literature
Project description:BACKGROUND:This study aimed to determine the optimal radiotherapy (RT) regimen for patients with clinical metastasis to the internal mammary lymph node (cIMN+) from breast cancer. METHODS:We retrospectively reviewed the medical records of 84 patients with cIMN+ breast cancer treated with curative surgery, taxane-based chemotherapy, and postoperative RT between January 2009 and December 2014. Postoperative RT was administered to the whole breast or chest wall using 50?Gy in 2?Gy fractions. Boost RT to the internal mammary lymph node (IMN) was administered at the physician's discretion. We categorized patients into two groups according to the IMN dose as follows: low-dose IMN RT (50.0-63.5?Gy) and high-dose IMN RT (63.6-70.4?Gy). RESULTS:After a median follow-up of 58?months (range, 12-111?months), IMN recurrence was observed in 2 patients (2.4%), and all IMN recurrences developed simultaneously with distant metastases. The 5-year locoregional recurrence-free survival, disease-free survival (DFS), and overall survival rates were 89.1, 72.0, and 81.2%, respectively. The triple-negative subtype, IMN size ?1.0?cm, old age, and low-dose IMN were significantly associated with poor DFS. Among the patients with IMN size ?1.0?cm, the 5-year DFS was significantly higher in those treated with high-dose IMN RT than in those treated with low-dose IMN RT (69.3% vs. 33.3%, p?=?0.019). CONCLUSIONS:IMN RT without IMN dissection resulted in favorable outcomes in cIMN+ breast cancer. For patients with a large IMN, a higher IMN radiation dose might be needed for disease control.
| S-EPMC7052982 | biostudies-literature
Project description:This study aimed to develop and validate a deep learning radiomics nomogram (DLRN) for the preoperative evaluation of axillary lymph node (ALN) metastasis status in patients with a newly diagnosed unifocal breast cancer. A total of 883 eligible patients with breast cancer who underwent preoperative breast and axillary ultrasound were retrospectively enrolled between April 1, 2016, and June 30, 2022. The training cohort comprised 621 patients from Hospital I; the external validation cohorts comprised 112, 87, and 63 patients from Hospitals II, III, and IV, respectively. A DLR signature was created based on the deep learning and handcrafted features, and the DLRN was then developed based on the signature and four independent clinical parameters. The DLRN exhibited good performance, yielding areas under the receiver operating characteristic curve (AUC) of 0.914, 0.929, and 0.952 in the three external validation cohorts, respectively. Decision curve and calibration curve analyses demonstrated the favorable clinical value and calibration of the nomogram. In addition, the DLRN outperformed five experienced radiologists in all cohorts. This has the potential to guide appropriate management of the axilla in patients with breast cancer, including avoiding overtreatment.
| S-EPMC10933422 | biostudies-literature
Project description:BackgroundLymph node metastasis is more likely in early-stage breast cancer with lower tumor-infiltrating lymphocyte (TIL) density. Therefore, we investigated the correlation between TILs and lymph node metastasis in cT1 breast cancer patients undergoing surgery and the usefulness of TILs in predicting sentinel lymph node metastasis (SLNM) in cT1N0M0 breast cancer.MethodsWe investigated 332 breast cancer patients who underwent surgery as the first-line treatment after preoperative diagnosis of cT1. A positive diagnosis of SLNM as an indication for axillary clearance was defined as macrometastasis in the sentinel lymph node (SLN) (macrometastasis: tumor diameter > 2 mm). Semi-quantitative evaluation of lymphocytes infiltrating the peritumoral stroma as TILs in primary tumor biopsy specimens prior to treatment was conducted.ResultsFor SLN biopsy (SLNB), a median of 2 (range, 1-8) SLNs were pathologically evaluated. Sixty cases (19.4%) of SLNM (macrometastasis: 46, micrometastasis: 16) were observed. Metastasis was significantly greater in breast cancers with tumor diameter > 10 mm than in those with diameter ≤ 10 mm (p = 0.016). Metastasis was significantly associated with lymphatic invasion (p < 0.001). These two clinicopathological factors correlated with SLNM even in patients diagnosed with cN0 (tumor size; p = 0.017, lymphatic invasion; p = 0.002). Multivariate analysis for SLNM predictors revealed lymphatic invasion (p = 0.008, odds ratio [OR] = 2.522) and TILs (p < 0.001, OR = 0.137) as independent factors.ConclusionsOur results suggest a correlation between lymph node metastasis and tumor immune-microenvironment in cT1 breast cancer. TIL density may be a predictor of SLNM in breast cancer without lymph node metastasis on preoperative imaging.
| S-EPMC7318528 | biostudies-literature
Project description:ObjectivesThe goal of this study was to assess the clinicopathological and ultrasound (US) features of breast cancer for predicting the risk of axillary lymph node metastasis.MethodsPatients with breast cancer were included in this retrospective, monocentric, observational study. Their preoperative ultrasound features, clinical data, laboratory results and postoperative pathologic results and immunophenotyping were collected. The association of these factors of breast cancer with axillary lymph node metastasis was evaluated by univariate and multivariate analysis.ResultsIn this study, 471 patients diagnosed with breast cancer at the First Affiliated Hospital of Xi'an Jiaotong University between July 2016 and September 2019 were collected, with a total of 471 nodules, of which 231(49.0%) had axillary lymph node metastasis, and 240(51.0%) did not. The parameters of hyperechoic halo, posterior acoustic decrease, microcalcification, carcinogenic embryonic antigen (CEA), cancer antigen-153 (CA153), CK5/6 (+), Ki67 (≥40%), AR (+) and histological grade (grade II and grade III) were significantly and independently associated with axillary lymph node metastasis (p < 0.05 for all).ConclusionsThe combination of ultrasound features, tumor markers, pathology, and immunohistochemistry can predict axillary lymph node metastasis in breast cancer patients.
| S-EPMC10657709 | biostudies-literature
Project description:BackgroundLymph node metastasis is a significant problem in breast cancer, and its underlying molecular mechanism is still unclear. The purpose of this study is to research the molecular mechanism and to explore the key RNAs and pathways that mediate lymph node metastasis in breast cancer.MethodsGSE100453 and GSE38167 were downloaded from the Gene Expression Omnibus (GEO) database and 569 breast cancer statistics were also downloaded from the TCGA database. Differentially expressed miRNAs were calculated by using R software and GEO2R. Gene ontology and Enriched pathway analysis of target mRNAs were analyzed by using the Database for Database of Annotation Visualization and Integrated Discovery (DAVID) and R software. The protein-protein interaction (PPI) network was performed according to Metascape, String, and Cytoscape software.ResultsIn total, 6 differentially expressed miRNAs were selected, and 499 mRNAs were identified after filtering. The research of the Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated that mRNAs enriched in certain tumor pathways. Also, certain hub mRNAs were highlighted after constructed and analyzed the PPI network. A total of 3 out of 6 miRNAs had a significant relationship with the overall survival (P < .05) and showed a good ability of risk prediction model of over survival.ConclusionsBy utilizing bioinformatics analyses, differently expressed miRNAs were identified and constructed a complete gene network. Several potential mechanisms and therapeutic and prognostic targets of lymph node metastasis were also demonstrated in breast cancer.
| S-EPMC7523764 | biostudies-literature