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1.
Clin Lung Cancer ; 23(5): 410-418, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35649817

RESUMO

INTRODUCTION: Plasma cfDNA-based mutation analysis has shown disease-monitoring potential in various cancers. We assessed the potential of cfDNA-based EGFR mutation testing as a monitoring tool in patients with NSCLC. PATIENTS AND METHODS: Patients with NSCLC harboring EGFR mutations receiving first-line treatment as per institutional protocol were enrolled. EGFR mutation status was determined using plasma samples at baseline and post treatment initiation. Patients in whom EGFR mutation was detected or persisted after treatment initiation were considered circulating tumor DNA (ctDNA)-positive. Progression-free survival (PFS) and overall survival (OS) for ctDNA-positive and negative patients post treatment initiation were the primary endpoints; concordance for baseline EGFR status between tissue and plasma and proportion of patients who were ctDNA-positive post treatment initiation were the secondary endpoints. RESULTS: We enrolled 158 patients; 76 received gefitinib, and 82 received gefitinib plus chemotherapy. Median follow-up duration was 42 months. About 25% of patients were ctDNA-positive post treatment initiation. Median PFS for ctDNA-negative patients post treatment initiation was 14 (95% confidence interval [CI], 12.0-17.0) months, while that for ctDNA-positive patients was 8 (95% CI, 6.0-10.0) months. Median OS for ctDNA-negative patients post treatment initiation was 27 (95% CI, 24.0-32.0) months, while that for ctDNA-positive patients was 15 (95% CI, 11.0-19.0) months. Concordance at baseline between tissue and plasma samples was 75.4%. CONCLUSION: Plasma-based EGFR mutation detection post treatment initiation can be used as a predictive marker for outcome in patients with EGFR-mutant NSCLC receiving first-line treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Humanos , Biópsia Líquida , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico
2.
Biol Direct ; 17(1): 15, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668531

RESUMO

This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.


Assuntos
Neoplasias Gastrointestinais , Medicina de Precisão , Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Mutação
4.
J Immunother Cancer ; 10(6)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35710297

RESUMO

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56-82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1-24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11-33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.


Assuntos
Instabilidade de Microssatélites , Neoplasias Pancreáticas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fatores Imunológicos , Imunoterapia , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Estudos Retrospectivos
5.
Artigo em Inglês | MEDLINE | ID: mdl-35732498

RESUMO

Liquid biopsy is considered an alternative to standard next-generation sequencing (NGS) of solid tumor samples when biopsy tissue is inadequate for testing or when testing of a peripheral blood sample is preferred. A common assumption of liquid biopsies is that the NGS data obtained on circulating cell-free DNA is a high-fidelity reflection of what would be found by solid tumor testing. Here, we describe a case that challenges this widely held assumption. A patient diagnosed with lung carcinoma showed pathogenic IDH1 and TP53 mutations by liquid biopsy NGS at an outside laboratory. Subsequent in-house NGS of a metastatic lymph node fine-needle aspiration (FNA) sample revealed two pathogenic EGFR mutations. Morphologic and immunophenotypic assessment of the patient's blood sample identified acute myeloid leukemia, with in-house NGS confirming and identifying pathogenic IDH1, TP53, and BCOR mutations, respectively. This case, together with a few similar reports, demonstrates that caution is needed when interpreting liquid biopsy NGS results, especially if they are inconsistent with the presumptive diagnosis. Our case suggests that routine parallel sequencing of peripheral white blood cells would substantially increase the fidelity of the obtained liquid biopsy results.


Assuntos
Leucemia Mieloide Aguda , Neoplasias Pulmonares , Biópsia por Agulha Fina/métodos , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Achados Incidentais , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Biópsia Líquida/métodos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação
6.
Sci Rep ; 12(1): 10447, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35729208

RESUMO

Dying tumor cells shed DNA fragments into the circulation that are known as circulating tumor DNA (ctDNA). Liquid biopsy tests aim to detect cancer using known markers, including genetic alterations and epigenetic profiles of ctDNA. Despite various advantages, the major limitation remains the low fraction of tumor-originating DNA fragments in a high background of normal blood-cell originating fragments in the cell-free DNA (cfDNA) pool in plasma. Deep targeted sequencing of cfDNA allows for enrichment of fragments in known cancer marker-associated regions of the genome, thus increasing the chances of detecting the low fraction variant harboring fragments. Most targeted sequencing panels are designed to include known recurrent mutations or methylation markers of cancer. Here, we propose the integration of cancer-specific chromatin accessibility states into panel designs for liquid biopsy. Using machine learning approaches, we first identify accessible and inaccessible chromatin regions specific to each major human cancer type. We then introduce a score that quantifies local chromatin accessibility in tumor relative to blood cells and show that this metric can be useful for prioritizing marker regions with higher chances of being detected in cfDNA for inclusion in future panel designs.


Assuntos
Ácidos Nucleicos Livres , DNA Tumoral Circulante , Biomarcadores Tumorais/genética , Cromatina/genética , DNA Tumoral Circulante/genética , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Mutação
7.
ACS Sens ; 7(6): 1698-1711, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35658424

RESUMO

Placental extracellular vesicles (EVs) play an essential role in pregnancy by protecting and transporting diverse biomolecules that aid in fetomaternal communication. However, in preeclampsia, they have also been implicated in contributing to disease progression. Despite their potential clinical value, current technologies cannot provide a rapid and effective means of differentiating between healthy and diseased placental EVs. To address this, a fabrication process called laser-induced nanostructuring of SERS-active thin films (LINST) was developed to produce scalable nanoplasmonic substrates that provide exceptional Raman signal enhancement and allow the biochemical fingerprinting of EVs. After validating the performance of LINST substrates with chemical standards, placental EVs from tissue explant cultures were characterized, demonstrating that preeclamptic and normotensive placental EVs have classifiably distinct Raman spectra following the application of advanced machine learning algorithms. Given the abundance of placental EVs in maternal circulation, these findings encourage immediate exploration of surface-enhanced Raman spectroscopy (SERS) of EVs as a promising method for preeclampsia liquid biopsies, while this novel fabrication process will provide a versatile and scalable substrate for many other SERS applications.


Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , Feminino , Humanos , Lasers , Biópsia Líquida , Placenta/patologia , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/patologia , Gravidez
8.
Pathol Oncol Res ; 28: 1610103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35665409

RESUMO

Collection and analysis of circulating tumor DNA (ctDNA) is one of the few methods of liquid biopsy that measures generalizable and tumor specific molecules, and is one of the most promising approaches in assessing the effectiveness of cancer care. Clinical assays that utilize ctDNA are commercially available for the identification of actionable mutations prior to treatment and to assess minimal residual disease after treatment. There is currently no clinical ctDNA assay specifically intended to monitor disease response during treatment, partially due to the complex challenge of understanding the biological sources of ctDNA and the underlying principles that govern its release. Although studies have shown pre- and post-treatment ctDNA levels can be prognostic, there is evidence that early, on-treatment changes in ctDNA levels are more accurate in predicting response. Yet, these results also vary widely among cohorts, cancer type, and treatment, likely due to the driving biology of tumor cell proliferation, cell death, and ctDNA clearance kinetics. To realize the full potential of ctDNA monitoring in cancer care, we may need to reorient our thinking toward the fundamental biological underpinnings of ctDNA release and dissemination from merely seeking convenient clinical correlates.


Assuntos
DNA Tumoral Circulante , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Docetaxel , Humanos , Biópsia Líquida/métodos , Mutação , Neoplasia Residual
9.
Biomed Pharmacother ; 150: 113064, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35658234

RESUMO

Clinically, cancer drug therapy is still dominated by chemotherapy drugs. Although the emergence of targeted drugs has greatly improved the survival rate of patients with advanced cancer, drug resistance has always been a difficult problem in clinical cancer treatment. At the current level of medicine, most drugs cannot escape the fate of drug resistance. With the emergence and development of gene detection, liquid biopsy ctDNA technology, and single-cell sequencing technology, the molecular mechanism of tumor drug resistance has gradually emerged. Drugs can also be updated in response to drug resistance mechanisms and bring higher survival benefits. The use of new drugs often leads to new mechanisms of resistance. In this review, the multi-molecular mechanisms of drug resistance are introduced, and the overcoming of drug resistance is discussed from the perspective of the tumor microenvironment.


Assuntos
Neoplasias , Medicina de Precisão , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Biópsia Líquida , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Microambiente Tumoral
10.
Cancer Res ; 82(12): 2213-2215, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35702889

RESUMO

Forty-five years ago, Cancer Research published the study by Leon and colleagues in which the authors described the observation of increased levels of cell-free DNA (cfDNA) in the serum of patients with cancer as compared with healthy individuals, with the highest serum levels in patients with metastatic cancer. Most interestingly was the correlation between serum DNA concentrations and therapy outcome: Increased serum DNA levels were associated with poor response to treatment, whereas decreases in DNA levels during treatment appeared to be a sign of better prognosis. Since the discovery of the prognostic value of blood DNA, much research has been focused on the characterization of cfDNA to understand its origins and increase the sensitivity and specificity of using cfDNA as a prognostic and predictive marker in the battle against cancer. Tumor-specific cfDNA markers that were discovered include genetic alterations, chromosomal aberrations, epigenetic modifications, and DNA fragmentation size. In recent years, due to the development of highly sensitive molecular technologies, cfDNA-based assays are now being introduced into the clinic as the so called "liquid biopsy." The advantages of a liquid biopsy over traditional biopsy and imaging have led to the implementation in the clinic for early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Despite Leon and colleagues' initial skepticism about the potential diagnostic value of serum DNA, cfDNA-based liquid biopsy has become one of the most important tools for personalized cancer treatment. See related article by Leon and colleagues, Cancer Res 1977;37:646-50.


Assuntos
Ácidos Nucleicos Livres , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , DNA , Humanos , Biópsia Líquida/métodos , Recidiva Local de Neoplasia
11.
J Clin Invest ; 132(12)2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35703177

RESUMO

Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.


Assuntos
DNA Tumoral Circulante , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Humanos , Biópsia Líquida , Mutação , Neoplasia Residual , Medicina de Precisão
12.
Annu Rev Anal Chem (Palo Alto Calif) ; 15(1): 107-121, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35696523

RESUMO

Cancer remains one of the leading causes of death, and early detection of this disease is crucial for increasing survival rates. Although cancer can be diagnosed following tissue biopsy, the biopsy procedure is invasive; liquid biopsy provides an alternative that is more comfortable for the patient. While blood, urine, and cerebral spinal fluid can all be used as a source of liquid biopsy, saliva is an ideal source of body fluid that is readily available and easily collected in the most noninvasive manner. Characterization of salivary constituents in the disease setting provides critical data for understanding pathophysiology and the evaluation of diagnostic potential. The aim of saliva diagnostics is therefore to develop a rapid and noninvasive detection of oral and systemic diseases that could be used together with compact analysis systems in the clinic to facilitate point-of-care diagnostics.


Assuntos
Neoplasias , Saliva , Biomarcadores Tumorais/análise , Detecção Precoce de Câncer , Humanos , Biópsia Líquida , Neoplasias/diagnóstico , Saliva/química
13.
Anal Chem ; 94(24): 8766-8773, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35670775

RESUMO

Aptamer-functionalized microfluidic interfaces hold great potential for liquid biopsies owing to their programmable nature. However, most previous studies have focused on development of multivalent aptamers to improve binding affinity, while ignoring aptamer orientation on microfluidic interfaces, resulting in suboptimal accessibility and affinity. Herein, we report a Cubic DNA Nanostructure (CDN)-programmed strategy to precisely control the orientation and valency of the Aptamer on a microfluidic interface (CDN-Apt-Chip) for enhancing the capture and release of circulating tumor cells (CTCs). We demonstrate that the ordered orientation and multivalent configuration can synergistically increase the binding affinity of aptamers toward CTCs. By using CDN-Apt-Chip, we successfully isolated CTCs from the peripheral blood of T-cell leukemia patients and discriminated T-cell leukemia patients from healthy volunteers. Furthermore, the captured CTCs were nondestructively released via nuclease treatment. We then performed T-cell receptor sequencing on the released cells to demonstrate the compatibility with downstream analysis. Overall, this study provides a new paradigm for interface regulation of functional microfluidic chips and advances the clinical translation of aptamer-based liquid biopsy.


Assuntos
Técnicas Analíticas Microfluídicas , Células Neoplásicas Circulantes , Linhagem Celular Tumoral , Separação Celular/métodos , DNA , Humanos , Biópsia Líquida , Técnicas Analíticas Microfluídicas/métodos , Microfluídica , Células Neoplásicas Circulantes/patologia
14.
Clin Chim Acta ; 532: 95-114, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35667477

RESUMO

Cancer remains a common health issue having significant socioeconomic burden worldwide. Despite the awareness campaigns, cancer cases continue to increase due to an aging population and lack of early detection biomarkers. Accordingly, much research has focused on non-traditional approaches which include novel imaging modalities and liquid biopsy. In addition, a considerable number of biomacromolecules as well as other biomarkers have been identified to further explore their potential use as diagnostic, prognostic and therapeutic tools. In this review, we provide an update on these new findings and explore their clinical application in cancer.


Assuntos
Células Neoplásicas Circulantes , Idoso , Biomarcadores Tumorais , Humanos , Biópsia Líquida , Células Neoplásicas Circulantes/patologia , Prognóstico
15.
JCO Precis Oncol ; 6(1): e2100321, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35721584

RESUMO

Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set. METHODS: Tempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests. RESULTS: Records from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame. CONCLUSION: We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.


Assuntos
Neoplasias da Mama , Ácidos Nucleicos Livres , Neoplasias da Mama/genética , Ácidos Nucleicos Livres/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Biópsia Líquida , Mutação
16.
BMC Cancer ; 22(1): 605, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655145

RESUMO

BACKGROUND: Hypomethylation of long interspersed nuclear element 1 (LINE-1) is characteristic of various cancer types, including colorectal cancer (CRC). Malfunction of several factors or alteration of methyl-donor molecules' (folic acid and S-adenosylmethionine) availability can contribute to DNA methylation changes. Detection of epigenetic alterations in liquid biopsies can assist in the early recognition of CRC. Following the investigations of a Hungarian colon tissue sample set, our goal was to examine the LINE-1 methylation of blood samples along the colorectal adenoma-carcinoma sequence and in inflammatory bowel disease. Moreover, we aimed to explore the possible underlying mechanisms of global DNA hypomethylation formation on a multi-level aspect. METHODS: LINE-1 methylation of colon tissue (n = 183) and plasma (n = 48) samples of healthy controls and patients with colorectal tumours were examined with bisulfite pyrosequencing. To investigate mRNA expression, microarray analysis results were reanalysed in silico (n = 60). Immunohistochemistry staining was used to validate DNA methyltransferases (DNMTs) and folate receptor beta (FOLR2) expression along with the determination of methyl-donor molecules' in situ level (n = 40). RESULTS: Significantly decreased LINE-1 methylation level was observed in line with cancer progression both in tissue (adenoma: 72.7 ± 4.8%, and CRC: 69.7 ± 7.6% vs. normal: 77.5 ± 1.7%, p ≤ 0.01) and liquid biopsies (adenoma: 80.0 ± 1.7%, and CRC: 79.8 ± 1.3% vs. normal: 82.0 ± 2.0%, p ≤ 0.01). However, no significant changes were recognized in inflammatory bowel disease cases. According to in silico analysis of microarray data, altered mRNA levels of several DNA methylation-related enzymes were detected in tumours vs. healthy biopsies, namely one-carbon metabolism-related genes-which met our analysing criteria-showed upregulation, while FOLR2 was downregulated. Using immunohistochemistry, DNMTs, and FOLR2 expression were confirmed. Moreover, significantly diminished folic acid and S-adenosylmethionine levels were observed in parallel with decreasing 5-methylcytosine staining in tumours compared to normal adjacent to tumour tissues (p ≤ 0.05). CONCLUSION: Our results suggest that LINE-1 hypomethylation may have a distinguishing value in precancerous stages compared to healthy samples in liquid biopsies. Furthermore, the reduction of global DNA methylation level could be linked to reduced methyl-donor availability with the contribution of decreased FOLR2 expression.


Assuntos
Adenoma , Neoplasias Colorretais , Receptor 2 de Folato , Doenças Inflamatórias Intestinais , Adenoma/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , DNA/metabolismo , Metilação de DNA , Receptor 2 de Folato/genética , Receptor 2 de Folato/metabolismo , Ácido Fólico , Humanos , Biópsia Líquida , RNA Mensageiro/metabolismo , S-Adenosilmetionina/metabolismo
17.
Int J Mol Sci ; 23(11)2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35682905

RESUMO

Tumor biopsy can identify prognostic biomarkers for metastatic uveal melanoma (UM), however aqueous humor (AH) liquid biopsy may serve as an adjunct. This study investigated whether the AH of UM eyes has sufficient circulating tumor DNA (ctDNA) to perform genetic analysis. This is a case series of 37 AH samples, taken before or after radiation, and one tumor wash sample, from 12 choroidal and 8 ciliary body (CB) melanoma eyes. AH was analyzed for nucleic acid concentrations. AH DNA and one tumor wash sample underwent shallow whole-genome sequencing followed by Illumina sequencing to detect somatic copy number alterations (SCNAs). Four post-radiation AH underwent targeted sequencing of BAP1 and GNAQ genes. Post-radiation AH had significantly higher DNA and miRNA concentrations than paired pre-radiation samples. Highly recurrent UM SCNAs were identified in 0/11 post-radiation choroidal and 6/8 post-radiation CB AH. SCNAs were highly concordant in a CB post-radiation AH with its matched tumor (r = 0.978). BAP1 or GNAQ variants were detected in 3/4 post-radiation AH samples. AH is a source of ctDNA in UM eyes, particularly in post-radiation CB eyes. For the first time, UM SCNAs and mutations were identified in AH-derived ctDNA. Suggesting that AH can serve as a liquid biopsy for UM.


Assuntos
Melanoma , Neoplasias Uveais , Humor Aquoso , Humanos , Biópsia Líquida , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Mutação , Recidiva Local de Neoplasia , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
18.
Target Oncol ; 17(3): 329-341, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35696014

RESUMO

BACKGROUND: Reliable biomarkers that can be serially monitored to predict treatment response to immune checkpoint inhibitors (ICIs) are still an unmet need. Here, we present a multiplex immunofluorescence (IF) assay that simultaneously detects circulating tumor cells (CTCs) and assesses CTC expression of programmed death ligand-1 (PD-L1) and interferon regulatory factor 1 (IRF-1) as a candidate biomarker related to ICI use. OBJECTIVE: To assess the potential of CTC PD-L1 and IRF-1 expression as candidate biomarkers for patients with advanced epithelial solid tumors receiving ICIs. PATIENTS AND METHODS: We tested the IF CTC assay in a pilot study of 28 patients with advanced solid tumors who were starting ICI. Blood for CTC evaluation was obtained prior to starting ICI, after a single cycle of therapy, and at the time of radiographic assessment or treatment discontinuation. RESULTS: At baseline, patients with 0-1 CTCs had longer progression-free survival (PFS) compared to patients with ≥ 2 CTCs (4.3 vs 1.3 months, p = 0.01). The presence of any PD-L1+ CTCs after a single dose of ICI portended shorter PFS compared to patients with no CTCs or PD-L1- CTCs (1.2 vs 4.2 months, p = 0.02); the presence of any PD-L1+ or IRF-1+ CTCs at time of imaging assessment or treatment discontinuation also was associated with shorter PFS (1.9 vs 5.5 months, p < 0.01; 1.6 vs 4.7 months, p = 0.05). CTC PD-L1 and IRF-1 expression did not correlate with tumor tissue PD-L1 or IRF-1 expression. Strong IRF-1 expression in tumor tissue was associated with durable (≥ 1 year) radiographic response (p = 0.02). CONCLUSIONS: Based on these results, CTC PD-L1 and IRF-1 expression is of interest in identifying ICI resistance and warrants further study.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Fator Regulador 1 de Interferon/metabolismo , Biópsia Líquida , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Projetos Piloto
19.
Front Immunol ; 13: 792046, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757760

RESUMO

Liquid biopsy has been rapidly developed in recent years due to its advantages of non-invasiveness and real-time sampling in cancer prognosis and diagnosis. Exosomes are nanosized extracellular vesicles secreted by all types of cells and abundantly distributed in all types of body fluid, carrying diverse cargos including proteins, DNA, and RNA, which transmit regulatory signals to recipient cells. Among the cargos, exosomal proteins have always been used as immunoaffinity binding targets for exosome isolation. Increasing evidence about the function of tumor-derived exosomes and their proteins is found to be massively associated with tumor initiation, progression, and metastasis in recent years. Therefore, exosomal proteins and some nucleic acids, such as miRNA, can be used not only as targets for exosome isolation but also as potential diagnostic markers in cancer research, especially for liquid biopsy. This review will discuss the existing protein-based methods for exosome isolation and characterization that are more appropriate for clinical use based on current knowledge of the exosomal biogenesis and function. Additionally, the recent studies for the use of exosomal proteins as cancer biomarkers are also discussed and summarized, which might contribute to the development of exosomal proteins as novel diagnostic tools for liquid biopsy.


Assuntos
Exossomos , Vesículas Extracelulares , Neoplasias , Biomarcadores Tumorais/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Biópsia Líquida/métodos , Neoplasias/metabolismo
20.
Adv Exp Med Biol ; 1379: 369-387, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35761000

RESUMO

Early cancer screening and effective diagnosis is the most effective form to diminish the number of cancer-related deaths. Liquid biopsy constitutes an attractive alternative to tumor biopsy due to its non-invasive nature and sample accessibility, which permits effective screening and patient monitoring. Within the plethora of biomarkers present in circulation, liquid biopsy has mainly been performed by analyzing circulating tumor cells, and more recently, extracellular vesicles. Tracking these biological particles could provide valuable insights into cancer origin, progression, treatment efficacy, and patient prognosis. Microfluidic devices have emerged as viable solutions for point-of-care cancer screening and monitoring due to their user-friendly operation, low operation costs, and capability of processing, quantifying, and analyzing these bioparticles in a single device. However, the size difference between cells and exosomes (micrometer vs nanometer) requires an adaptation of microfluidic isolation approaches, particularly in label-free methodologies governed by particle and fluid mechanics. This chapter will explore the theory behind particle isolation and sorting in different microfluidic techniques necessary to guide researchers into the design and development of such devices.


Assuntos
Exossomos , Células Neoplásicas Circulantes , Biomarcadores Tumorais/análise , Exossomos/patologia , Humanos , Biópsia Líquida , Microfluídica/métodos , Células Neoplásicas Circulantes/patologia
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