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1.
Proc Jpn Acad Ser B Phys Biol Sci ; 96(3): 107-121, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32161209

RESUMEN

During the past decade, substantial progress has been made in the field of the genetics of myelodysplastic syndromes (MDS). These comprise a group of chronic myeloid neoplasms with abnormal cell morphology and progression to acute myeloid leukemia (AML), where revolutionary sequencing technologies have played a major role. Through extensive sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations involved in the pathogenesis of MDS has been revealed, along with their impacts on clinical phenotype and prognosis. The most frequently affected molecules are involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. These mutations show strong positive and negative correlations with each other, suggesting the presence of functional interactions between mutations, which dictate disease progression. Because these mutations are associated with disease phenotype, drug response, and clinical outcomes, it is essential to be familiar with MDS genetics not only for better understanding of MDS pathogenesis but also for management of patients.


Asunto(s)
ADN de Neoplasias/genética , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Metilación de ADN , Reparación del ADN , ADN de Neoplasias/metabolismo , Progresión de la Enfermedad , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide de Fase Crónica/genética , Mutación , Fenotipo , Pronóstico , Empalme del ARN , Análisis de Secuencia de ADN , Transducción de Señal
2.
Mutat Res ; 819-820: 111694, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32120135

RESUMEN

Precise execution of the cell division cycle is vital for all organisms. The Cyclin dependent kinases (CDKs) are the main cell cycle drivers, however, their activities must be precisely fine-tuned to ensure orderly cell cycle progression. A major regulatory axis is guarded by WEE1 kinase, which directly phosphorylates and inhibits CDK1 and CDK2. The role of WEE1 in the G2/M cell-cycle phase has been thoroughly investigated, and it is a focal point of multiple clinical trials targeting a variety of cancers in combination with DNA-damaging chemotherapeutic agents. However, the emerging role of WEE1 in S phase has so far largely been neglected. Here, we review how WEE1 regulates cell-cycle progression highlighting the importance of this kinase for proper S phase. We discuss how its function is modulated throughout different cell-cycle stages and provide an overview of how WEE1 levels are regulated. Furthermore, we outline recent clinical trials targeting WEE1 and elaborate on the mechanisms behind the anticancer efficacy of WEE1 inhibition. Finally, we consider novel biomarkers that may benefit WEE1-inhibition approaches in the clinic.


Asunto(s)
Proteína Quinasa CDC2/genética , Proteínas de Ciclo Celular/genética , Quinasa 2 Dependiente de la Ciclina/genética , Replicación del ADN , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Proteínas Tirosina Quinasas/genética , Antineoplásicos/uso terapéutico , Proteína Quinasa CDC2/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Ensayos Clínicos como Asunto , Quinasa 2 Dependiente de la Ciclina/metabolismo , Daño del ADN , Reparación del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , ADN de Neoplasias/metabolismo , Humanos , Mitosis/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Fase S/efectos de los fármacos , Fase S/genética , Transducción de Señal
3.
Mutat Res ; 819-820: 111690, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32120136

RESUMEN

The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBß) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy.


Asunto(s)
ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Terapia Molecular Dirigida/métodos , Neoplasias/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Daño del ADN , Reparación del ADN/efectos de los fármacos , ADN de Neoplasias/metabolismo , Rayos gamma/uso terapéutico , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Resultado del Tratamiento , Proteínas ras/genética , Proteínas ras/metabolismo
4.
J Cancer Res Clin Oncol ; 146(5): 1115-1124, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32144534

RESUMEN

PURPOSE: Aberrant DNA methylation could regulate the expression of tumor suppressor gene DLEC1 and oncogene PBX3 and was related to the occurrence and prognosis of gastric cancer (GC). In this study, the associations between DLEC1 and PBX3 promoter methylation in peripheral blood leukocytes (PBLs) and the risk and prognosis of GC were investigated. METHODS: The methylation status of DLEC1 and PBX3 promoter in PBLs of 368 GC cases and 382 controls was detected by the methylation-sensitive high-resolution melting (MS-HRM) method. Logistic and Cox regression were adopted to analyze the associations of DLEC1 and PBX3 methylation with GC risk and prognosis, respectively. Confounding biases were controlled by propensity score (PS). RESULTS: Compared with negative methylation (Nm), DLEC1-positive methylation (Pm) was associated with increased GC risk in PS (OR 2.083, 95% CI 1.220-3.558, P = 0.007), but PBX3 Pm was not associated with GC risk. In the elderly group (≥ 60 years), DLEC1 Pm was associated with increased GC risk (OR 2.951, 95% CI 1.426-6.104, P = 0.004). The combined effects between DLEC1 methylation and consumption of dairy products, fried food intake and Helicobacter pylori (H. pylori) infection on GC risk were discovered (ORc 3.461, 95% CI 1.847-6.486, P < 0.001, ORc 3.246, 95% CI 1.708-6.170, P < 0.001 and ORc 2.964, 95% CI 1.690-5.197, P < 0.001, respectively). Furthermore, DLEC1 and PBX3 methylation were not associated with GC prognosis. CONCLUSION: DLEC1 methylation in PBLs and the combined effects of gene-environment can influence GC risk.


Asunto(s)
Proteínas de Homeodominio/genética , Leucocitos/metabolismo , Proteínas Proto-Oncogénicas/genética , Neoplasias Gástricas/genética , Proteínas Supresoras de Tumor/genética , Estudios de Casos y Controles , Metilación de ADN , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/genética , Helicobacter pylori/aislamiento & purificación , Humanos , Leucocitos/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Neoplasias Gástricas/sangre , Neoplasias Gástricas/patología
5.
Med Sci Monit ; 26: e921040, 2020 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-32200389

RESUMEN

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.


Asunto(s)
ADN Tumoral Circulante/sangre , ADN de Neoplasias/genética , Nanotecnología/métodos , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/genética , ADN de Neoplasias/sangre , Detección Precoz del Cáncer/métodos , Humanos , Biopsia Líquida , Neoplasias/sangre , Neoplasias/diagnóstico
6.
Crit Rev Oncol Hematol ; 146: 102879, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32005411

RESUMEN

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/líquido cefalorraquídeo , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN de Neoplasias/metabolismo , Glioma/líquido cefalorraquídeo , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , ADN de Neoplasias/genética , Genes Relacionados con las Neoplasias/genética , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/patología
7.
Nucleic Acids Res ; 48(5): 2287-2302, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32002550

RESUMEN

Accumulating evidence has demonstrated that transcriptional regulation is affected by DNA methylation. Understanding the perturbation of DNA methylation-mediated regulation between transcriptional factors (TFs) and targets is crucial for human diseases. However, the global landscape of DNA methylation-mediated transcriptional dysregulation (DMTD) across cancers has not been portrayed. Here, we systematically identified DMTD by integrative analysis of transcriptome, methylome and regulatome across 22 human cancer types. Our results revealed that transcriptional regulation was affected by DNA methylation, involving hundreds of methylation-sensitive TFs (MethTFs). In addition, pan-cancer MethTFs, the regulatory activity of which is generally affected by DNA methylation across cancers, exhibit dominant functional characteristics and regulate several cancer hallmarks. Moreover, pan-cancer MethTFs were found to be affected by DNA methylation in a complex pattern. Finally, we investigated the cooperation among MethTFs and identified a network module that consisted of 43 MethTFs with prognostic potential. In summary, we systematically dissected the transcriptional dysregulation mediated by DNA methylation across cancer types, and our results provide a valuable resource for both epigenetic and transcriptional regulation communities.


Asunto(s)
Biomarcadores de Tumor/genética , ADN de Neoplasias/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Factores de Transcripción/genética , Biomarcadores de Tumor/metabolismo , Islas de CpG , Metilación de ADN , ADN de Neoplasias/metabolismo , Femenino , Redes Reguladoras de Genes , Genoma Humano , Humanos , Masculino , Anotación de Secuencia Molecular , Neoplasias/metabolismo , Neoplasias/mortalidad , Neoplasias/patología , Análisis de Supervivencia , Factores de Transcripción/clasificación , Factores de Transcripción/metabolismo , Transcriptoma
8.
Life Sci ; 248: 117467, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32105706

RESUMEN

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.


Asunto(s)
ADN de Neoplasias/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucocitos/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Adulto , Alelos , Animales , Grupo de Ascendencia Continental Asiática , Línea Celular Tumoral , Proliferación Celular , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN de Neoplasias/biosíntesis , Femenino , Xenoinjertos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/etnología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucocitos/patología , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Polimorfismo Genético , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal
9.
Ann Hematol ; 99(3): 459-475, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31932899

RESUMEN

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.


Asunto(s)
ADN de Neoplasias , Vesículas Extracelulares , Leucemia Mieloide Aguda , Mutación , Adolescente , Niño , Preescolar , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino
10.
Crit Rev Oncol Hematol ; 146: 102863, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31935617

RESUMEN

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.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Biopsia Líquida/métodos , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Plaquetas/patología , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Ácidos Nucleicos Libres de Células/genética , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Mutación , Medicina de Precisión , Inhibidores de Proteínas Quinasas/uso terapéutico
11.
Ann Hematol ; 99(3): 527-537, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31989250

RESUMEN

Azacitidine (AZA) is a DNA hypomethylation agent administered in myeloid neoplasms; however, there is still a lack of established predictors of response. We studied 113 patients with myelodysplastic syndromes (n = 85) or acute myeloid leukemia (n = 28) who received AZA to assess the predictive value on response of clinical features, cytogenetics, and molecular markers. Overall, 46 patients (41%) responded to AZA. Platelet doubling after the first AZA cycle was associated with a better response (68% vs. 32% responders, P = 0.041). Co-occurrence of chromosome 7 abnormalities and 17p deletion was associated with a worse response (P = 0.039). Pre-treatment genetic mutations were detected in 98 patients (87%) and methylation of CDKN2B and DLC-1 promoters were detected in 50 (44%) and 37 patients (33%), respectively. Patients with SF3B1 mutations showed a better response to AZA (68% vs. 35% responders, P = 0.008). In contrast, subjects with mutations in transcription factors (RUNX1, SETBP1, NPM1) showed a worse response (20% vs. 47% responders, P = 0.014). DLC-1 methylation pre-treatment was associated with poor clinical features and its reduction post-treatment resulted in a better response to AZA in MDS patients (P = 0.037). In conclusion, we have identified several predictors of response to AZA that could help select the best candidates for this treatment.


Asunto(s)
Azacitidina/administración & dosificación , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Metilación de ADN/efectos de los fármacos , ADN de Neoplasias , Proteínas Activadoras de GTPasa , Síndromes Mielodisplásicos , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/metabolismo , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Supervivencia sin Enfermedad , Femenino , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/mortalidad , Tasa de Supervivencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
12.
J Cancer Res Clin Oncol ; 146(4): 935-944, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31894386

RESUMEN

PURPOSE: This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring ALK fusion genes. METHODS: We interrogated the genomic profile of 1652 patients with lung cancer who underwent targeted next-generation sequencing to screen for candidate oncogenic drivers using histological specimens acquired from January 2016 to December 2018. RESULTS: ALK fusions were identified in 101 NSCLC patients, and 52 of them were diagnosed before the age of 50 years (52/367, 14.2%). Of the 52 patients with early-onset disease, 22 (42.3%) were male and 43 (82.7%) never smoked; the median patient age was 44 years (range 28-50 years). The most frequently occurring ALK fusion partner was EML4, which was identified in 80.8% (42/52) of young patients. Compared to the older patients, patients with early-onset disease were more likely to harbor EML4-ALK variant 1 (38.5% vs. 14.3%; P = 0.007). We also identified rare ALK fusions, including CHRNA7-ALK, TACR1-ALK, HIP1-ALK, DYSF-ALK and ITGAV-ALK, in patients with early-onset disease, and patients with these fusions responded well to crizotinib treatment. A statistically significant difference was observed in progression-free survival (PFS) between the young patients and older patients who received crizotinib as the first-line therapy (17.5 months vs 9.0 months, P = 0.048). However, the median PFS of young patients harboring concurrent TP53 mutations was only 6.2 months. CONCLUSION: Unique genetic characteristics were found in ALK-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant TP53 mutations may not have a significant response to treatment.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Crizotinib/uso terapéutico , Fusión Génica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Adulto , Factores de Edad , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , ADN de Neoplasias/genética , Femenino , Reordenamiento Génico , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Supervivencia sin Progresión , Transcriptoma , Proteína p53 Supresora de Tumor/genética
13.
Proc Natl Acad Sci U S A ; 117(4): 2020-2031, 2020 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-31937660

RESUMEN

The DNA-binding protein CCCTC-binding factor (CTCF) and the cohesin complex function together to shape chromatin architecture in mammalian cells, but the molecular details of this process remain unclear. Here, we demonstrate that a 79-aa region within the CTCF N terminus is essential for cohesin positioning at CTCF binding sites and chromatin loop formation. However, the N terminus of CTCF fused to artificial zinc fingers was not sufficient to redirect cohesin to non-CTCF binding sites, indicating a lack of an autonomously functioning domain in CTCF responsible for cohesin positioning. BORIS (CTCFL), a germline-specific paralog of CTCF, was unable to anchor cohesin to CTCF DNA binding sites. Furthermore, CTCF-BORIS chimeric constructs provided evidence that, besides the N terminus of CTCF, the first two CTCF zinc fingers, and likely the 3D geometry of CTCF-DNA complexes, are also involved in cohesin retention. Based on this knowledge, we were able to convert BORIS into CTCF with respect to cohesin positioning, thus providing additional molecular details of the ability of CTCF to retain cohesin. Taken together, our data provide insight into the process by which DNA-bound CTCF constrains cohesin movement to shape spatiotemporal genome organization.


Asunto(s)
Neoplasias de la Mama/metabolismo , Factor de Unión a CCCTC/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , ADN de Neoplasias/metabolismo , Sitios de Unión , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Factor de Unión a CCCTC/genética , Proteínas de Ciclo Celular/genética , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Genoma Humano , Humanos , Unión Proteica , Dominios Proteicos , Células Tumorales Cultivadas
14.
Acta Cytol ; 64(1-2): 147-154, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-30995656

RESUMEN

As the value of molecular testing of cancer specimens increases, the number of tests imposed on tumor specimens also increases, often in tension with the amount of tumor material available. To develop and validate molecular assays for limited specimens, there are specific concerns that must be addressed, including DNA quality, quantity, and abundance; the number of targets/ability to multiplex; and the analytical sensitivity and specificity of the assay itself. Ultimately, weighing these considerations during assay validation in the overall context of clinical utility and laboratory workflow is critical for delivering the highest level of personalized care to patients.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Neoplasias/diagnóstico , ADN de Neoplasias/genética , Humanos , Neoplasias/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
15.
Bull Cancer ; 107(1): 113-128, 2020 Jan.
Artículo en Francés | MEDLINE | ID: mdl-31353136

RESUMEN

In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.


Asunto(s)
Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación Missense , Mutación Puntual , Antineoplásicos/uso terapéutico , Dominio Catalítico , Toma de Decisiones Clínicas , ADN de Neoplasias/análisis , Resistencia a Antineoplásicos/genética , Sustitución de Medicamentos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Biología Molecular , Dominios Proteicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Rol
16.
Gut ; 69(2): 243-251, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31085554

RESUMEN

OBJECTIVE: Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. DESIGN: Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. RESULTS: CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal-epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. CONCLUSIONS: H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Neoplasias Gástricas/genética , Medios de Cultivo Condicionados , Metilación de ADN , ADN de Neoplasias/genética , Epigenómica/métodos , Ontología de Genes , Estudio de Asociación del Genoma Completo/métodos , Humanos , Histona Demetilasas con Dominio de Jumonji/deficiencia , Mutación , Nicho de Células Madre , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Células Tumorales Cultivadas
17.
Gynecol Oncol ; 156(1): 203-210, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31757465

RESUMEN

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.


Asunto(s)
Proteínas Serina-Treonina Quinasas/genética , Neoplasias del Cuello Uterino/genética , Grupo de Ascendencia Continental Asiática/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Femenino , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Valor Predictivo de las Pruebas , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología
18.
J Cancer Res Clin Oncol ; 146(1): 273-285, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31641854

RESUMEN

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.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Transducción de Señal
19.
J Cancer Res Clin Oncol ; 146(2): 407-416, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31696302

RESUMEN

INTRODUCTION: Next-generation sequencing (NGS)-based assays to understand various mutations and co-occurrence of genomic alterations in non-small cell lung cancer (NSCLC) have enabled understanding of treatment impact on clinical outcomes. METHODS: This retrospective study was conducted in 1353 formalin-fixed paraffin-embedded (FFPE) tissues from surgically resected, pre-TKI-treated NSCLC patients with identified gene alterations. Genomic DNA and RNA extraction was followed by NGS library preparation and sequencing using the Ion Ampliseq Colon and Lung Cancer Gene Panel V2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel. RESULTS: A total of 2328 alterations in 25 genes were detected from the 1293 patients. DNA mutations and RNA fusions co-occurred in 27 patients with TP53 being the most common co-occurring DNA mutation (43.8%) with concurrent ALK fusions. Analysis of the 975 patients with EGFR mutations revealed that the incidence of dual EGFR L858R/T790M mutations was higher compared to EGFR 19del/T790M, and the mean allele fraction (MAF) of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. CONCLUSION: NSCLC patients represented genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways. This diverse mutational profile may have key clinical and research implications for understanding the variability of treatment outcome in pre-TKI-treated NSCLC population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , ADN de Neoplasias/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , ARN Neoplásico/genética , Estudios Retrospectivos , Adulto Joven
20.
Cell Prolif ; 53(1): e12718, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31721355

RESUMEN

OBJECTIVES: We investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment. MATERIALS AND METHODS: Prostate cancer cell lines and epithelial RWPE-1 cells were used in the study. Cell viability, wound-healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA-seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti-tumour effects of pentamidine in vivo. RESULTS: Pentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells. CONCLUSIONS: Pentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria-targeted therapeutic agent for prostate cancer.


Asunto(s)
Proliferación Celular/efectos de los fármacos , ADN Mitocondrial , ADN de Neoplasias , Mitocondrias , Pentamidina/farmacología , Neoplasias de la Próstata , Animales , Proliferación Celular/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Ratones , Ratones Desnudos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Células PC-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de Xenoinjerto
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