The individual risk to progression is unclear for intermediate risk prostate cancer patients. To assess their risk to progression, we examined the level of genomic instability in circulating tumor cells (CTCs) using quantitative three-dimensional (3D) telomere analysis. Data of CTCs from 65 treatment-naïve patients with biopsy-confirmed D’Amico-defined intermediate risk prostate cancer were compared to radical prostatectomy pathology results, which provided a clinical endpoint to the study and confirmed pre-operative pathology or demonstrated upgrading. Hierarchical centroid cluster analysis of 3D pre-operative CTC telomere profiling placed the patients into three subgroups with different potential risk of aggressive disease. Logistic regression modeling of the risk of progression estimated odds ratios with 95% confidence interval (CI) and separated patients into “stable” vs. “risk of aggressive” disease. The receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.77, while prostate specific antigen (PSA) (AUC of 0.59) and Gleason 3 + 4 = 7 vs. 4 + 3 = 7 (p > 0.6) were unable to predict progressive or stable disease. The data suggest that quantitative 3D telomere profiling of CTCs may be a potential tool for assessing a patient’s prostate cancer pre-treatment risk.
Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability.
Finally, this study showed that PA has powerful antitumor activity against AML cells suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.
Background Telomere dysfunction results in aneuploidy, and ongoing chromosomal abnormalities. The three-dimensional (3D) nuclear organization of telomeres allows for a distinction between normal and tumor cells. On the other hand, aurora kinase genes (AURKA and AURKB) play an important role regulating the cell cycle. A correlation between overexpression of aurora kinase genes and clinical aggressiveness has been demonstrated in different types of neoplasias. To better understand cellular and molecular mechanisms of CML evolution, it was examined telomere dysfunction (alterations in the 3D nuclear telomere architecture), and the expression levels of AURKA and AURKB genes in two clinical distinct subgroups of CML samples, from the same patient. Methods Eighteen CML patients, in total, 36 bone marrow samples (18 patients, chronic vs. accelerated/blast phase) were eligible for 3D telomeric investigations. Quantitative 3D imaging, cytologic diagnosis and cytogenetic determination of additional chromosomal abnormalities were assessed according to standard protocols. Results Using TeloView software, two CML subgroups were defined based on their 3D telomeric profiles, reflecting the different stages of the disease (chronic vs. accelerated/blast phase). Statistical analyses showed significant differences between the CML subgroups (p < 0.001). We also found that AURKA and AURKB mRNA were expressed at significantly higher levels in both CML subgroups, when compared with healthy donors. Our findings suggest that the evolution of CML progresses from a low to a high level of telomere dysfunction, that is, from an early stage to a more aggressive stage, followed by disease transformation, as demonstrated by telomere, additional chromosomal abnormalities, and gene expression profile dynamics. Conclusions Thus, we demonstrated that 3D telomere organization, in accordance with the genomic instability observed in CML samples were able to distinguish subgroup CML patients. Classifying CML patients based on these characteristics might represent an important strategy to define better therapeutic strategies.
Advances in the development of precision medicine for prostate cancer patients rely on accurate identification of the genomic features underlying a patient's tumor. Genomic analysis of circulating tumor cells (CTCs) could provide a unique and accessible representation of tumor diversity, however for the use of CTCs as a less-invasive sampling of prostate cancer and as biomarkers for patient stratification and selection of targeted therapy, complex platforms are necessary to ensure an efficient enrichment (isolation), detection (identification-imaging) and characterization strategies (molecular profiles). In this study, we combined a filtration-based CTC isolation technology with prostate cancer cell-specific antibodies to identify the prostate cancer CTCs. After identification, we performed the 3D telomere profiling prior to laser microdissection for whole genome sequencing of singles CTCs from 11 localized high-risk prostate cancer patient samples (36 CTCs in total). We identified unique and common somatic single nucleotide variants (SSNVs) and copy number alterations (CNAs) that can be used to predict high-risk lethal prostate cancer and treatment response in patients with clinically localized high- risk prostate cancers. The distribution of telomeres intensities show a range between 0 to 190.000 (a.u) and telomeres parameters were similar as described previously for high risk patients by our group. We analyzed 36 CTCs from 11 different patient samples and compared with normal lymphocytes from the same patient using whole genome sequencing (WGS). We identified 184 common mutated genes in all CTCs and two mutated genes with the same base pair (bp) mutation (PMS2 and EIF2AK4). We also identified 503 consensus mutations found in all patient but not in all CTCs and 1728 unique mutations found in all or any CTCs of only one patient, showing the heterogeneity that arises in single cells. The list of genes affected are all involved in potential pathways for tumor development such as immune system, signal transduction, homeostasis, gene expression, chromatin organization, DNA repair, cell cycle, programmed cell death, cell-cell communication and others. MCPH1, also known as BRIT1, is a key regulatory gene of the DNA damage response pathway and was mutated in all CTCs from prostate patients. MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR) genes which promotes also genomic Instability. Those mutations can be closely linked with the genomic instability we found assessing the telomere profiles. The CDH17 gene is a member of the cadherin superfamily and in contrast to classic cadherins, such as E- and N-cadherin, LI-cadherin possess biological functions distinct from classic cadherins and reduced expression of LI-cadherin is closely associated with tumor progression and lymph node metastasis of human colorectal carcinoma. These mutations were also found in all CTCs. All this information is needed for individualized therapy and predict drug resistance, phenotypic transition which is heterogeneous from cell to cell from patient to patient. Citation Format: Aline Rangel Pozzo. Whole genome sequencing of single circulating tumor cells from localized high-risk prostate cancer patients: Laser microdissection and 3Dtelomere profile [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3535.
Background: Telomere dysfunction results in aneuploidy, and ongoing chromosomal abnormalities. The three-dimensional (3D) nuclear organization of telomeres allows for a distinction between normal and tumor cells. On the other hand, aurora kinase genes (AURKA and AURKB) play an important role regulating the cell cycle. A correlation between overexpression of aurora kinase genes and clinical aggressiveness has been demonstrated in different types of neoplasias. To better understand cellular and molecular mechanisms of CML evolution, it was examined telomere dysfunction (alterations in the 3D nuclear telomere architecture), and the expression levels of AURKA and AURKB genes in two clinical distinct subgroups of CML samples, from the same patient. Methods: Eighteen CML patients, in total, 36 bone marrow samples (18 patients, chronic vs. accelerated/blast phase) were eligible for 3D telomeric investigations. Quantitative 3D imaging, cytologic diagnosis and cytogenetic determination of additional chromosomal abnormalities were assessed according to standard protocols. Results: Using TeloView software, two CML subgroups were defined based on their 3D telomeric profiles, reflecting the different stages of the disease (chronic vs. accelerated/blast phase). Statistical analyses showed significant differences between the CML subgroups (p<0.001). We also found that AURKA and AURKB mRNA were expressed at significantly higher levels in both CML subgroups, when compared with healthy donors. Our findings suggest that the evolution of CML progresses from a low to a high level of telomere dysfunction, that is, from an early stage to a more aggressive stage, followed by disease transformation, as demonstrated by telomere, additional chromosomal abnormalities, and gene expression profile dynamics. Conclusions: Thus, we demonstrated that 3D telomere organization, in accordance with the genomic instability observed in CML samples were able to distinguish subgroup CML patients. Classifying CML patients based on these characteristics might represent an important strategy to define better therapeutic strategies.
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