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1.
Med Sci Monit ; 26: e921040, 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32200389

RESUMO

Circulating tumor DNA (ctDNA) describes the fragmented DNA released from tumor cells into the blood. The ctDNA may have the same genetic changes as the primary tumor. Currently, ctDNA has become a popular biomarker for diagnosis, treatment, real-time clinical response monitoring, and prognosis, for solid tumors. Detection of ctDNA is minimally invasive, and repeat sampling can easily be performed. However, due to its low quality and short DNA fragment length, ctDNA detection still faces challenges and requires highly sensitive analytical techniques. Recently, liquid biopsies for the analysis of circulating tumor cells (CTCs) and circulating tumor-derived exosomes have been studied, and nanotechnology techniques have rapidly developed. Compared to traditional analytical methods, these nanotechnology-based platforms have the advantages of sensitivity, multiplex detection, simplicity, miniaturization, and automation, which support their potential use in clinical practice. This review aims to discuss the recent nanotechnological strategies for ctDNA analysis and the design of reliable techniques for ctDNA detection and to identify the potential clinical applications.


Assuntos
DNA Tumoral Circulante/sangue , DNA de Neoplasias/genética , Nanotecnologia/métodos , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , DNA de Neoplasias/sangue , Detecção Precoce de Câncer/métodos , Humanos , Biópsia Líquida , Neoplasias/sangue , Neoplasias/diagnóstico
2.
Ann Hematol ; 99(3): 459-475, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31932899

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by a collection of genetic and epigenetic changes. As a consequence, AML can evolve towards more aggressive subtypes during treatment, which require additional therapies to prevent future relapse. As we have previously detected double-stranded DNA (dsDNA) in tumor-derived extracellular vesicles (EVs), in this current study we attempted to evaluate the potential diagnostic applications of AML EV-dsDNA derived from primary bone marrow and peripheral blood plasma samples. EVs from plasma of 29 pediatric AML patients (at initial diagnosis or during treatment) were isolated by ultracentrifugation, after which dsDNA was extracted from obtained EVs and analyzed for leukemia-specific mutations using next generation sequencing (NGS) and GeneScan-based fragment-length analysis. In 18 out of 20 patients, dsDNA harvested from EVs mirrored the (leukemia-specific) mutations found in the genomic DNA obtained from primary leukemia cells. In the nanoparticle tracking analysis (NTA), a decrease in EV numbers was observed in patients after treatment compared with initial diagnosis. Following treatment, in 75 samples out of the 79, these mutations were no longer detectable in EV-dsDNA. In light of our results, we propose the use of leukemia-derived EV-dsDNA as an additional measure for mutational status and, potentially, treatment response in pediatric AML.


Assuntos
DNA de Neoplasias , Vesículas Extracelulares , Leucemia Mieloide Aguda , Mutação , Adolescente , Criança , Pré-Escolar , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino
3.
Crit Rev Oncol Hematol ; 146: 102863, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31935617

RESUMO

Lung cancer is the most frequent cancer for males and third most frequent cancer for females. Targeted therapy drugs based on molecular alterations, such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors are important part of treatment of NSCLC. However, the quality of the available tumor biopsy and/or cytology material is sometimes not adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of tumor-educated platelet (TEP) as a liquid biopsy in lung cancer patients. The development of sensitive and accurate techniques have made it possible to detect the specific genetic alterations for which targeted therapies are already available. Liquid biopsy offers opportunities to detect resistance mechanisms at an early stage. To conclude, tumor-educated platelet has the potential to be used as liquid biopsy for a variety of clinical and investigational applications.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Biópsia Líquida/métodos , Neoplasias Pulmonares/patologia , Biomarcadores Tumorais/genética , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Ácidos Nucleicos Livres/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Mutação , Medicina de Precisão , Inibidores de Proteínas Quinases/uso terapêutico
4.
J Cancer Res Clin Oncol ; 146(1): 273-285, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31641854

RESUMO

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). METHODS: We extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed. RESULTS: The AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664-5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543-4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04). CONCLUSIONS: Our results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Transdução de Sinais
5.
Nat Med ; 25(12): 1928-1937, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768066

RESUMO

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Genômica , Neoplasias/sangue , Adulto , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Análise Mutacional de DNA , DNA de Neoplasias/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Neoplasias/patologia
6.
Nat Med ; 25(9): 1415-1421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501609

RESUMO

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias Gastrointestinais/sangue , Biópsia Líquida , Autopsia , Ácidos Nucleicos Livres/genética , Estudos de Coortes , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Exoma
7.
Ann Hematol ; 98(12): 2719-2727, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31486880

RESUMO

Aberrant promoter methylation of RASSF6 and RASSF10 occurs at a high frequency in acute lymphoblastic leukemia (ALL). Because of the complexity of the current minimal residual disease (MRD) detecting-methods, the DNA methylation status of the RASSF6 and RASSF10 genes could potentially become biomarkers for the assessment of MRD levels in ALL patients. The promoter methylation status of RASSF6 and RASSF10 was assessed by using methylation-specific PCR (MSP) in the DNA isolated from 280 peripheral blood (PB) samples taken at the time of diagnosis, day 14, 28, and from the subsequent 30-month follow-ups of 45 adult ALL patients. The relative methylation level obtained during the follow-ups by MSP was compared to the MRD results obtained by the amplification of IG/TCR clonal rearrangements using the allele-specific quantitative-PCR (ASO-PCR) assay. Frequently, RASSF6 was methylated in B-ALL, and RASSF10 was methylated in T-ALL. The applicability and accuracy of the assays were increased when these markers were combined (91.1% and 93.8%, respectively). When a cutoff was defined for the PCR-MRD level, results of the 30 months of MRD detection showed a significant correlation between the PCR and MSP techniques (r = 0.848; p < 0.001). Due to the high applicability, the non-invasiveness, and promising prospect of longitudinal assessment, the DNA methylation status of the RASSF6 and RASSF10 genes could be potential biomarkers for the assessment of residual disease in PB of patients with ALL.


Assuntos
Biomarcadores Tumorais , Metilação de DNA , DNA de Neoplasias , Proteínas Monoméricas de Ligação ao GTP , Leucemia-Linfoma Linfoblástico de Células Precursoras , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Monoméricas de Ligação ao GTP/sangue , Proteínas Monoméricas de Ligação ao GTP/genética , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Supressoras de Tumor/sangue , Proteínas Supressoras de Tumor/genética
8.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 64-72, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472049

RESUMO

Breast cancer is a malignant tumor that occurs in the glandular epithelial tissues of the breast. It is one of the most common malignant tumors in women. This study was aimed at investigating the role of cell-free DNA (cfDNA) as a potential biomarker for breast cancer diagnosis. Patients with primary breast cancer (n =110) were enrolled in the experimental group, 95 patients with benign breast tumors were in control group 1, while 90 healthy volunteers were in control group 2. Quantitative PCR was used to determine cfDNA concentration and integrity in each group. The cfDNA levels in different groups and their relationship with clinical features of breast cancer patients were analyzed. Receiver operational curves were established to analyze sensitivity and specificity of cfDNA concentration, cfDNA integrity, CEA, CA125 and CA15-3. The cfDNA concentration and cfDNA integrity of the experimental group were significantly higher than those of control groups 1 and 2. The cfDNA concentration and integrity in plasma of experimental group after chemotherapy were significantly lower than those before chemotherapy. While CEA and CA15-3 expressions were significantly correlated with cfDNA concentration, CA125 expression was significantly correlated with cfDNA integrity. Results from ROC curve analysis showed that the sensitivity and specificity of cfDNA concentration and integrity were higher than those of traditional tumor biomarkers. These results indicate that cfDNA concentration and integrity are significantly higher in primary breast cancer patients than in benign breast tumor patients and healthy people. Thus, cfDNA may serve as a potential biomarker of breast cancer.


Assuntos
Neoplasias da Mama/sangue , Ácidos Nucleicos Livres/sangue , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ácidos Nucleicos Livres/genética , DNA de Neoplasias/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
9.
Oncol Rep ; 42(4): 1580-1588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364747

RESUMO

The objectives of the present study were to obtain the multigene mutation spectra of female breast cancer patients in Northeast China, to explore the correlation between mutations and clinicopathological characteristics, and to identify genetic mutations that correlate with the prognosis and survival of breast cancer patients. An Ion Torrent sequencing platform was used to detect mutations, including 31 known gene mutations associated with breast cancer, in 621 specimens from 286 breast cancer patients. A total of 286 patients were enrolled in this study. Eleven harmful/pathogenic gene mutations were found in 54.2% (155/286) of the patients, and 179 somatic nonsynonymous mutations were detected. Approximately 5.6% (16/286) of the patients carried two or more gene mutations. Among the 11 pathogenic gene mutations, those in PIK3CA were the most common and were detected in 65.4% (117/179) of the patients; TP53 gene mutations were the second most common and were detected in 20.7% (37/179) of the patients. Additional mutations were found in AKT (14/179; 7.8%) and PTEN (4/179; 2.2%), and mutations in the remaining 7 genes were each detected in approximately 0.6% (1/179) of the patients. Excluding 6 cases of breast ductal carcinoma in situ, the remaining 280 breast cancer cases were divided into four groups by molecular subtype, and the mutation frequencies of the 11 breast cancer­associated genes differed among the four groups. Furthermore, these 280 breast cancer cases were divided into two clinically relevant therapeutic groups: the HR+/HER2­ and triple­negative groups. The triple­negative group had a high frequency of TP53 mutations (21.8%) and a low frequency of PIK3CA mutations (21.8%), whereas the HR+/HER2­ group harbored TP53 mutations at a low frequency (10.1%) and PIK3CA mutations at a high frequency (50.0%). Cancerous, paracancerous, and normal tissues were collected from 72 patients and subjected to next­generation sequencing. The types and frequencies of somatic nonsynonymous mutations differed among the three studied tissue types, reflecting the genetic heterogeneity of different tissues from the same individual. In addition, tissues from 70 patients (excluding 2 patients with ductal carcinoma in situ) were divided into four groups according to molecular subtype, and the gene mutation frequencies in cancerous, paracancerous, and normal tissues differed among the four groups. After normalization, gene mutations were detected at a higher rate in cancerous tissues than in paracancerous and normal tissues in all groups, except for the HER2­positive group (which had a small sample size). In addition, Cox multivariate analyses of clinicopathological data, gene sequencing results, and 5­year survival rates of the 286 patients showed that gene mutations in the PTEN­PI3K/AKT signaling pathway were independently associated with a poor prognosis (P<0.05). In conclusion, mutations in the PTEN­PI3K/AKT signaling pathway may be valuable in the prediction of the prognosis and survival of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Família Multigênica , Mutação , Adulto , Neoplasias da Mama/enzimologia , China , Análise Mutacional de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Lesões Pré-Cancerosas/enzimologia , Lesões Pré-Cancerosas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
10.
Cancer Treat Rev ; 78: 31-41, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326635

RESUMO

Current classification and treatment of lung cancer rely increasingly on molecular and genetic testing. Obtaining tumor tissue is not always feasible and multiple biopsies are undesirable. In response to the demand for non-invasive molecular and genetic testing in cancer care, several liquid biopsy technologies, including circulating DNA (ctDNA), have been developed. ctDNA analysis is now technically feasible to be carried out in large scales and integrated into clinical practice owing to the advances in technology. Despite the challenges in improving test accuracy and cost-effectiveness, there are huge potentials for ctDNA analysis in lung cancer management. This review focuses on the clinical utility of ctDNA analysis in lung cancer, including early detection, monitoring treatment response and detecting residual disease, identification of genetic determinants for targeted therapy, and predicting efficacy of immune checkpoint blockade.


Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , DNA de Neoplasias/sangue , Neoplasias Pulmonares/diagnóstico , Humanos , Biópsia Líquida , Neoplasias Pulmonares/sangue
11.
Orv Hetil ; 160(30): 1167-1177, 2019 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-31327245

RESUMO

The incidence and mortality of colorectal cancer (CRC) are considerably high in Central European countries, it is the second most common cancer in both men and women in Hungary with 10,000 newly registered patients per year. These data indicate the necessity of new screening methods that are more comfortable for patients, hence the compliance can be increased. Cell-free DNA (cfDNA) level in blood is elevated in certain physiological conditions, such as pregnancy or high physical activity. Furthermore, cfDNA concentration alterations can also be detected in some pathological processes; increased cfDNA amount was observed in autoimmune and inflammatory diseases, as well as in various cancers including CRC. Numerous studies about origin, function, and mechanism of cfDNA can be found in the scientific literature. In this review, we aimed to describe the quantitative and qualitative changes of cfDNA, to present its functions, and to provide an overview of the available diagnostic applications for CRC. CfDNA can be released to the circulatory system via apoptosis, necrosis or by direct secretions by living cells. In cancer patients, cfDNA can originate from healthy and cancer cells, hence genetic (e.g. mutations in APC, KRAS, BRAF) and epigenetic (e.g. methylation in SEPT9, SFRP1) alterations of tumor cells can be examined in cfDNA fraction. Several high-throughput, sensitive and even automated methods are available providing opportunity to perform standardized sample preparation and to analyse biomarker candidates quantitatively. These enhancements can help to develop alternative screening methods that can be easily integrated into the clinical practice and can contribute to early cancer detection. Orv Hetil. 2019; 160(30): 1167-1177.


Assuntos
Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/diagnóstico , DNA de Neoplasias/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/sangue , Metilação de DNA , DNA de Neoplasias/sangue , Feminino , Humanos , Hungria , Masculino
12.
Pediatr Blood Cancer ; 66(11): e27948, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31347788

RESUMO

BACKGROUND: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT. PROCEDURE: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing. RESULTS: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. CONCLUSIONS: Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Genes Neoplásicos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Terapia Neoadjuvante , Análise de Sequência de DNA , Carga Tumoral/efeitos dos fármacos , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , DNA de Neoplasias/sangue , Avaliação de Medicamentos , Monitoramento de Medicamentos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/sangue , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Proteínas de Neoplasias/genética , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Esplenectomia , Condicionamento Pré-Transplante
13.
Isr Med Assoc J ; 21(6): 394-398, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31280508

RESUMO

BACKGROUND: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA). OBJECTIVES: To analyze osimertinib outcomes according to T790M testing method. METHODS: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups. RESULTS: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8-17.5) and 9.1 months (95%Cl 5.3-12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9-25.5) and 13.8 months (95%Cl 7.7-27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50-2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45-3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016-2017. CONCLUSIONS: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA Tumoral Circulante/sangue , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Israel , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Resultado do Tratamento
14.
Urology ; 132: 1-9, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31207303

RESUMO

We reviewed the literature for the biologic, prognostic, and predictive significance of circulating prostate cancer tumor cells (CTCs), and circulating tumor DNA in the blood of metastatic castration resistant prostate cancer patients. CTCs demonstrate robust prognostic value independent of PSA in predicting overall survival. The CTC androgen receptor variant receptor 7 phenotype predicts resistance to androgen receptor synthesis inhibitors and sensitivity to taxane based chemotherapy in metastatic castration resistant prostate cancer patients who are candidates for second line therapy. Research is rapidly pivoting toward circulating tumor DNA analysis because the approach is sensitive, prognostic, cost effective, and it can elucidate mechanisms of systemic therapy.


Assuntos
DNA de Neoplasias/sangue , Células Neoplásicas Circulantes/patologia , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Humanos , Biópsia Líquida , Masculino , Valor Preditivo dos Testes , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
15.
BMC Cancer ; 19(1): 465, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101027

RESUMO

BACKGROUND: Gene variants are dependable and sensitive biomarkers for target-specific therapies in breast cancer (BC). However, detection of mutations within tissues has many limitations. Plasma circulating free DNA (cfDNA) has been reported in many studies as an alternative tool for detection of mutations. But the diagnostic accuracy of cfDNA for most mutations in BC needs to be reviewed. This study was designed to perform comparative assessment of the diagnostic performance of cfDNA and DNA extracted from tissues for detection of single nucleotide variants (SNV) and copy number variants (CNV). METHODS: True-positive (TP), false-positive (FP), false-negative (FN), and true-negative (TN) values were extracted from each selected study. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. Subgroup analysis and single study omitted analysis were performed to quantify and explain the study heterogeneity. RESULTS: Twenty eligible studies that involved 1055 cases were included in this meta-analysis. SNV studies in early breast cancer (EBC) subgroup are not suitable for meta-analysis owing to high heterogeneity. However, in advanced breast cancer (ABC) subgroup, the pooled sensitivity and specificity of detection of SNVs were 0.78 (0.71-0.84) and 0.92 (0.87-0.95), respectively. The summary receiver operative curve (SROC) exhibited an area under the curve (AUC) of 0.91(0.88-0.93). The pooled results of studies involving subgroups of PIK3CA, TP53, and ESR1 indicate that the diagnostic value of different genes is different, such as AUC for PIK3CA and TP53 were reported to be 0.96 (0.94-0.98) and 0.94 (0.91-0.95), respectively, and ESR1 had the lowest diagnostic value of 0.80 (0.76-0.83). Owing to the low sensitivity and AUC in the cases of CNV, there is no value for cfDNA-based detection of CNV based on insufficient amount of CNV data. CONCLUSION: This meta-analysis suggests that the detection of gene mutations in cfDNA have adequate diagnostic accuracy and can be used as an alternative to the tumor tissue for detection of SNV but not for CNV in BC yet.


Assuntos
Neoplasias da Mama/genética , Ácidos Nucleicos Livres/sangue , Variações do Número de Cópias de DNA , Análise Mutacional de DNA/métodos , DNA de Neoplasias/sangue , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Confiabilidade dos Dados , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Sensibilidade e Especificidade
16.
Cancer Res ; 79(10): 2462-2465, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31043377

RESUMO

Cancer is one of the leading causes of death worldwide. This life-threatening disease requires novel strategies for the early detection and therapy response prediction. Circulating DNA was first described 70 years ago. However, only the recent evolution in the PCR-based sequencing techniques allow the minimally invasive molecular profiling of circulating mutant DNA from small-volume "liquid biopsies" such as blood, urine, or saliva. In this article, we aim to summarize the fast-growing evidence for cfDNA and exosomal DNA as minimally invasive diagnostic markers in solid tumors and to highlight their opposing diagnostic advantages and disadvantages.


Assuntos
Ácidos Nucleicos Livres/genética , DNA de Neoplasias/sangue , Exossomos/genética , Biópsia Líquida , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Humanos , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias/genética , Reação em Cadeia da Polimerase/métodos
18.
Genet Test Mol Biomarkers ; 23(4): 264-269, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30986100

RESUMO

BACKGROUND: Qualitative and quantitative detection of circulating tumor DNA (ctDNA) is a liquid biopsy technology used for early cancer diagnosis. However, the plasma ctDNA content is extremely low, so it is difficult to detect somatic mutations of tumors using conventional sequencing methods. Target region sequencing (TRS) technology, through enrichment of the target genomic region followed by next generation sequencing, overcomes this challenge and has been widely used in ctDNA sequencing. METHODS: We designed a ctDNA sequencing panel to capture 128 tumor genes, and tested the performance of the panel by running TRS for ctDNA of a clear cell renal cell carcinoma (ccRCC) patient and 12 breast cancer patients. RESULTS: TRS using the new ctDNA panel at more than 500 × coverage depth achieved almost the same accuracy as traditional whole-exome sequencing (WES). PBRM1 p.L641V was detected in the plasma sample of the ccRCC patient with an allele frequency of 0.2%. The ctDNA of 12 breast cancer patients was sequenced at a depth of 500-fold, achieving 99.89% coverage; 34 genes were detected with mutations, including the drug target genes BRCA2, PTEN, TP53, APC, KDR, and NOTCH2. CONCLUSIONS: This TRS new ctDNA panel can be used to detect mutations in cell-free DNA from multiple types of cancer.


Assuntos
Neoplasias da Mama/genética , Carcinoma de Células Renais/genética , Biópsia Líquida/métodos , Adulto , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/diagnóstico , DNA Tumoral Circulante/análise , DNA Tumoral Circulante/sangue , DNA de Neoplasias/sangue , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNA
19.
Int J Radiat Oncol Biol Phys ; 104(4): 828-835, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951807

RESUMO

PURPOSE: Nivolumab improves survival in patients with metastatic melanoma. Unfortunately, most patients do not respond to this treatment. Preclinical data indicate that radiation therapy could work synergistically with nivolumab and improve response rates. METHODS AND MATERIALS: We conducted a phase 2 trial in 20 patients with inoperable or metastatic melanoma with ≥2 measurable lesions (Response Evaluation Criteria in Solid Tumors v1.1). Stereotactic body radiation therapy (SBRT) of 3 × 8 Gy to the largest lesion was delivered before the second nivolumab cycle. The primary endpoint was overall response rate (ORR) in the nonirradiated lesions (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included toxicity. An exploratory endpoint was mutant BRAF and NRAS circulating tumor DNA (ctDNA) on serial blood samples. RESULTS: An ORR of 45% was noted with 3 complete and 6 partial responses. Three patients experienced stable disease and 7 had progressive disease as best response. All patients with a complete response in the nonirradiated lesions exhibited a local complete response in the irradiated lesion. Grade 1 to 2 treatment-related adverse events (AEs) occurred in 17 patients; 3 patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred. ctDNA was detected in 8 patients, and changes corresponded to clinical response and suggested that a subset of patients with a low programmed death ligand-1 score only started responding after SBRT. CONCLUSIONS: We conclude that the combination treatment was well tolerated and led to an ORR of 45% in patients with metastatic or inoperable melanoma, similar to historical response rates of nivolumab monotherapy. Although underpowered, our data therefore do not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia/métodos , Melanoma/terapia , Nivolumabe/uso terapêutico , Radiocirurgia/métodos , Neoplasias Cutâneas/terapia , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/sangue , Quimiorradioterapia/efeitos adversos , DNA de Neoplasias/sangue , Esquema de Medicação , Feminino , GTP Fosfo-Hidrolases/sangue , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/sangue , Melanoma/patologia , Melanoma/secundário , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/sangue , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Radiocirurgia/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
20.
Cell Prolif ; 52(3): e12589, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30873683

RESUMO

In recent years, with the increase in cancer mortality caused by metastasis, and with the development of individualized and precise medical treatment, early diagnosis with precision becomes the key to decrease the death rate. Since detecting tumour biomarkers in body fluids is the most non-invasive way to identify the status of tumour development, it has been widely investigated for the usage in clinic. These biomarkers include different expression or mutation in microRNAs (miRNAs), circulating tumour DNAs (ctDNAs), proteins, exosomes and circulating tumour cells (CTCs). In the present article, we summarized and discussed some updated research on these biomarkers. We overviewed their biological functions and evaluated their multiple roles in human and small animal clinical treatment, including diagnosis of cancers, classification of cancers, prognostic and predictive values for therapy response, monitors for therapy efficacy, and anti-cancer therapeutics. Biomarkers including different expression or mutation in miRNAs, ctDNAs, proteins, exosomes and CTCs provide more choice for early diagnosis of tumour detection at early stage before metastasis. Combination detection of these tumour biomarkers may provide higher accuracy at the lowest molecule combination number for tumour early detection. Moreover, tumour biomarkers can provide valuable suggestions for clinical anti-cancer treatment and execute monitoring of treatment efficiency.


Assuntos
Biomarcadores Tumorais , Neoplasias/diagnóstico , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Metilação de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Detecção Precoce de Câncer/métodos , Exossomos/química , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Mutação , Proteínas de Neoplasias/análise , Neoplasias/sangue , Neoplasias/genética , Células Neoplásicas Circulantes/patologia , Valor Preditivo dos Testes , Prognóstico
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