Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes in telomere length may thus contribute to the development of various diseases including cancer. Understanding the role of telomeric DNA in carcinogenesis and detecting the presence of cell-free telomeric DNA (cf-telDNA) in body fluids offer a potential biomarker for novel cancer screening and diagnostic strategies. Liquid biopsy is becoming increasingly popular due to its undeniable benefits over conventional invasive methods. However, the organization and function of cf-telDNA in the extracellular milieu are understudied. This paper provides a review based on 3,398,017 cancer patients, patients with other conditions, and control individuals with the aim to shed more light on the inconsistent nature of telomere lengthening/shortening in oncological contexts. To gain a better understanding of biological factors (e.g., telomerase activation, alternative lengthening of telomeres) affecting telomere homeostasis across different types of cancer, we summarize mechanisms responsible for telomere length maintenance. In conclusion, we compare tissue- and liquid biopsy-based approaches in cancer assessment and provide a brief outlook on the methodology used for telomere length evaluation, highlighting the advances of state-of-the-art approaches in the field.
Circulating tumor cells (CTCs) play a pivotal role in tumor dissemination and progression, and are considered to be a critical part of the metastatic cascade. The aim of the present research article was to examine breast cancer-specific mutations in primary breast cancer (PBC) using targeted resequencing. A total of 78 patients with PBC were enrolled into this translational study. Reverse transcription-quantitative PCR assay for the expression of epithelial markers (CK19) or epithelial-to-mesenchymal transition (EMT)-related genes (TWIST1, SNAIL1, SLUG and ZEB1) was applied for identification of CTCs prior to surgery. Total DNA was isolated from fresh frozen primary tumors. Sequencing was performed by Agilent SureSelect target enrichment and Illumina paired-end sequencing on the MiSeq platform. The most commonly affected genes were TP53 (mutated in 21 tumors; 26.9%), followed by PIK3CA (mutated in 16 tumors; 20.5%) and BRCA1/2 (mutated in 7 tumors, BRCA1 n=2 and BRCA2 n=5; 9.0%). In our cohort, a significantly higher proportion of patients with epithelial CTCs harbored mutations in the BRCA1/2 genes in the tumor tissue. There were no mutations in specific genes associated with CTCs with the EMT phenotype. To the best of our knowledge, this study is the first to report a correlation between the presence of epithelial CTCs in the peripheral blood and mutations of the BRCA1/2 genes in primary tumor tissue.
Background: CTCs play a major role in tumor dissemination and progression, and represent one of the key components of the metastatic cascade. The aim of this study was to identify signaling pathways associated with presence of CTCs in primary breast cancer (PBC) patients using a comprehensive genomics approach. Methods: This translational study included 78 patients with PBC. CTCs were detected before surgery by quantitative RT-PCR assay for expression of epithelial (EP; CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total DNA and RNA were extracted, in parallel, from fresh frozen primary tumor and the microRNA and mRNA expression profiles were obtained using Human microRNA Microarray v21.0 and SurePrint G3 Human Gene Expression v3 (Agilent Technologies). Next generation sequencing (NGS) was performed by Illumina Multiplex Sequencing using MiSeq Sequencing Reagent Kit V3. Results:Mutations in BRCA1/2 genes in tumor tissue were more common in patients with epithelial CTCs (CTC_EP) compared to patients without epithelial CTCs in peripheral blood (23.5% vs. 0%, p = 0.02), while there were no mutations in specific genes associated with CTC with EMT phenotype (CTC_EMT).Further, we identified 90 genes and 7 miRs that were expressed at significantly different levels in tumors with presence of CTC_EP and 199 genes and 13 miRs specifically associated with CTC_EMT, compared to tumors with non-detectable CTCs. We also identified 39 overlapping genes and 7 miRs, that were expressed at significantly different levels in tumors with CTC_EP and/or CTC_EMT compared to tumors with non-detectable CTCs. Overlapping genes and miRs with highest different levels in expression were ATAD3A, TMEM201, DCPS, DOCK9-AS2, TRAF2 and miR-5195-3p, miR-188-5p, miR-6780a-5p, miR-6757-5p. Signalling pathways associated with these genomic alterations belong to several critically functional groups, such as immune response, signal transduction, cell proliferation, cell cycle progression, or apoptosis were significantly differentially based on CTCs status. Conclusions: We identified for the first time various genomic alterations in primary tumor tissue of PBC associated with different CTCs subpopulations in peripheral blood. We hypothesize that these genomic alterations could play a role in tumor dissemination and progression and might lead to identification of new therapeutic targets. Citation Format: Mego M, Tokar T, Minarik G, Hajduk M, Karaba M, Benca J, Sedlackova T, Repiska G, Krasnicanova L, Macuch J, Sieberova G, Pindak D, Cristofanilli M, Reuben JM, Jurisica I, Mardiak J. Comprehensive analysis of genomic alterations in tumor tissue associated with presence of various subpopulations of circulating tumor cells (CTCs) in primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-05.
e23022 Background: CTCs play major role in tumor dissemination and progression and represent one of the key component of metastatic cascade. MicroRNAs (miRs) are involved in regulation in several biological processes in cancer including invasion, epithelial-mesenchymal transition (EMT) and disease progression. The aim of this study was to identify miRs in primary tumor associated with presence of CTCs in peripheral blood (PB) in non-metastatic breast cancer patients. Methods: This translational study included 79 patients with primary breast cancer for whom fresh frozen tumor tissue and status of CTCs in peripheral blood were available. CTCs were detected before surgery by qRT-PCR assay for expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted from fresh frozen primary tumor and the expression profiles were obtained using Human microRNA Microarray v21.0 (Agilent Technologies). Results: We analyzed 48 (60.8%) tumor samples from patients with presence of CTCs in PB and 31 (39.2%) tumors with non-detectable CTCs. From CTCs positive patients, in 20 (41.7%) of them epithelial CTCs (EP_CTC) were detected while in 28 (38.3%) CTCs with EMT (CTC_EMT) phenotype were present. We identified 178 miRs that were expressed at significantly different levels (FDR < 0.05) in tumors with presence of any type of CTCs in PB compared to tumors with non-detectable CTCs. We also identified 174 and 137 miRs (33 overlapping) that were expressed at significantly different levels in tumors with EP_CTCs and CTC_EMT, respectively, compared to tumors with non-detectable CTCs. Overlapping miRs with highest different levels in expression (FDR < 0.01) were miR-3137, miR-3138, miR-3168, miR-605-5p, miR-6165 and miR-6790-5p. Conclusions: We identified for the first time miRs expressed in primary tumor associated with CTCs in peripheral blood in breast cancer patients. Moreover, we identified miRs specifically associated with various subpopulations of CTCs. We suppose, that these miRs could be involved in tumor dissemination and might lead to identification of new therapeutic targets. Study was supported by APVV-14-0327.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.