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Identifier 000451934
Title Προβλεπτική αξία των microRNAs (miRNAs) που σχετίζονται με την κατάσταση του καρκινικού λήθαργου για την όψιμη υποτροπή στον πρώιμο καρκίνο του μαστού
Alternative Title Dormancy related microRNAs (miRNAs) in the prediction of late relapse in early Breast Cancer
Author Στρατηγός, Μιχαήλ
Thesis advisor Μαυρουδής , Δημήτριος
Reviewer Αγγελάκη, Σοφία
Τσατσάνης, Χρήστος
Eelco de Bree
Θεοδωρόπουλος ,Παναγιώτης
Τζαρδή, Μαρία
Τόλια Μαρία
Abstract 1. Introduction Breast cancer is the most common malignancy (excluding skin cancer) and the second leading cause of death from malignancy in women after lung cancer. Despite significant advances in all available treatments (surgery, radiotherapy, systemic treatments), some patients still relapse and eventually die. During the first 5 years after diagnosis, the risk of recurrence is higher in hormone receptor negative tumors. The metastatic process consists of multiple steps that include local infiltration, intravascular dissemination of cancer cells, extravasation in target tissues and their proliferation. The concept of cancer dormancy and epithelial-to-mesenchymal transformation plays an important role in cancer biology and metastatic development. An increasing number of experimental and clinical data have shown that, among other things, these processes are regulated by miRNAs (non-coding monoclonal sequences of approximately 22 nucleotides that exercise post-transcriptional control of gene expression). The aim of this study was to investigate the expression of specific circulating miRNAs (miR-21, miR-23b, miR-190, miR-200b and miR-200c) in patients with early breast cancer, as well as their relationship with clinical outcomes. The results could identify groups of patients at increased risk of recurrence who may benefit from additional treatment. 2. Patients and methods This study included 209 patients with early breast cancer who underwent adjuvant chemotherapy in the Department of Medical Oncology, University General Hospital of Heraklion between 2003 and 2010. 23 healthy individuals were recruited as a control group. After surgery, plasma was collected before chemotherapy was initiated. Total RNA was isolated using Trizol LS (Ambion Life Technologies). Quantitative real-time PCR was then performed using the TaqMan miRNA Reverse Transcription kit and specific miRNA stem-loop primers. The mean expression levels for each miRNA were calculated by the 2-ΔCt method relative to the mean miR-23a levels. Patients with miRNA expression levels equal to or above the median value were characterized as having high expression, while patients with miRNA expression levels below the median value were characterized as having low expression. The relationship between circulating miRNA expression levels and disease-free survival (DFS) or overall survival (OS) was assessed using the Kaplan-Meier method, the log rank test (Mantel-Cox) and Cox proportional hazard regression models. To estimate the value of circulating miRNAs in predicting recurrence, ROC (receiver operating characteristics) curves were constructed and the area under the curve (AUC) was calculated. 3. Results For this analysis, plasma samples were collected from 155 patients with early breast cancer and 23 healthy women. After a median follow-up of 94.3 months, 49 patients relapsed, whereas 84 did not. Demographic and clinical characteristics were similar between patients who did not relapse and those who relapsed, except for the percentage of patients with tumors larger than 5 cm (T3) or at least 4 positive axillary lymph nodes, which was higher in patients with relapse (p = 0.015 and p = 0.003 respectively). Patients were classified into three groups according to clinical outcome: (i) patients who remained free of relapse during the entire follow-up period (n = 84), (ii) patients with early relapse, defined as relapse within 3 years after surgery (n = 23) and (iii) patients with late relapse, defined as relapse at least 5 years after surgery (n = 20). Finally, six patients experienced relapse between 3 and 5 years after surgery. miR-21 (p < 0.001), miR-23b (p = 0.028) and miR-200c (p < 0.001) expression were higher and miR-190 was lower (p = 0.013) in relapsed (n = 49), compared to non-relapsed patients (n = 84). Interestingly, miR-190 was lower (p = 0.0032) in patients with early relapse (at < 3 years; n = 23) compared to those without early relapse (n = 110). On the other hand, miR-21 and miR-200c were higher (p = 0.015 and p < 0.001, respectively) in patients with late relapse (relapse at &ge; 5 years; n = 20) as compared to non-relapsed patients. High miR-200c was associated with shorter disease-free survival (DFS) (p = 0.005) and high miR-21 with both shorter DFS and overall survival (OS) (p < 0.001 and p = 0.033, respectively) compared to low expression. ROC curve analysis revealed that miR-21, miR-23b, miR-190 and miR-200c discriminated relapsed from non-relapsed patients. A combination of of miR-21, miR-23b and miR-190 showed higher sensitivity and specificity in ROC analyses compared to each miRNA alone; accuracy was further improved by adding lymph node infiltration and tumor grade to the panel of three miRs (AUC 0.873). Furthermore, the combination of miR-200c, lymph node infiltration, tumor grade and estrogen receptor predicted late relapse (AUC 0.890). 4. Conclusions The results of our study indicate that some miRNAs associated with dormancy and metastasis are differentially expressed in early breast cancer patients who eventually relapse compared with those who do not. Our study is among the first to highlight the potential utility of these miRNAs as circulating predictive biomarkers in early breast cancer, as it provided the ability to predict recurrence up to years before development of clinically evident metastases, and evaluated their predictive value besides common clinicopathological parameters. Importantly, high expression of miR-21 and miR-200c was associated with shorter DFS compared with patients with low expression, while high expression of miR-21 was associated with shorter overall survival as well. Finally, our study provides potential insights into the procedures and pathways involved in the regulation of dormancy and metastasis in breast cancer. Our study has some limitations, as the results are derived from a relatively small group of patients and require validation in an independent cohort. Therefore, these results should be considered preliminary and warrant prospective validation in a larger cohort of patients with early diseas
Language Greek
Subject Καρκινικός λήθαργος
Issue date 2022-12-07
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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