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1.
Asian Pac J Cancer Prev ; 21(3): 593-598, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32212783

RESUMEN

OBJECTIVE: The transformation in cells at genetic levels stimulatesthe proliferation of cancer. The current review highlights the role of miRNA in management of cancer by altering processes of body at cellular levels. METHODS: A deep research on the literature available till date for miRNA in cancer was conducted using various medical sites like PubMed, MEDLINE from internet and data was collected. The articles were majorly preferred in English language. RESULTS: The development of normal cells into cancerous cells is a multivalent procedure highlighting numerous responsible factors. During the progression of cancer, the role of oncogene and tumor suppressor genes outshines at different levels of tumorogenesis. Metastasis poses highest threat in cancer progression and fabricates obstacles to clinicians and researchers in preventing formation of tumor on secondary sites. The mesenchymal-epithelial transition (MET) and epithelial mesenchymal transition (EMT) induce dissemination and ultimately progression of cancer. CONCLUSION: A comprehensive knowledge of the altered genes and the mechanism by which they induce formation of tumor is essential as they contribute in proliferating cancer at various stages, aggravating clinical symptoms. Hence miRNAs can be efficiently employed as an emerging treatment therapy for cancer.


Asunto(s)
MicroARNs/genética , Neoplasias/genética , Animales , Ciclo Celular , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Humanos , Neoplasias/patología , Transcripción Genética
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 117-123, 2020 Feb 28.
Artículo en Chino | MEDLINE | ID: mdl-32131950

RESUMEN

Tumors are highly complex systems. Understanding the compositions and functions of the tumor immune microenvironment is a prerequisite for effective tumor immunotherapy. Single-cell RNA sequencing can detect the transcriptome of a cell at the resolution of single-cell level,describe its functional status,and thus deepen the understanding of the composition and function of different cell clusters in tumor immune microenvironment. This article reviews the application of single-cell RNA sequencing in research on tumor immune microenvironment.


Asunto(s)
Neoplasias/genética , Neoplasias/inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Inmunoterapia , Transcriptoma
3.
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 Precóz del Cáncer/métodos , Humanos , Biopsia Líquida , Neoplasias/sangre , Neoplasias/diagnóstico
4.
Life Sci ; 248: 117473, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32114007

RESUMEN

MicroRNAs (miRNAs) are a group of tiny molecules of 18-22 nucleotide long noncoding RNA that regulate the post-transcriptional gene expression through translational inhibition and/or mRNA destabilization. Because of their involvement in important developmental processes, it is highly likely that the altered expression of miRNAs could be associated with abnormal conditions like suboptimal growth or diseases. Thus, the expression of miRNAs can be used as biomarkers in pathophysiological conditions. Recently, a handful of miRNAs are detected in cell-free conditions including biofluids and cell culture media and they exhibit specific expression patterns that are associated with altered physiological conditions. Extracellular miRNAs are not only extremely stable outside cells in a variety of biofluids but also they are easy to acquire. These characteristics led to the idea of using extracellular miRNAs as a potential biomarker for the onset and prognosis of cancer. Although miRNAs have been proposed as a potential diagnostic tool for cancer detection, their application in the routine clinical investigation is yet to come. First, this review will provide an insight into the extracellular miRNAs, particularly, their release mechanisms and characteristics, and the potential of extracellular miRNAs as a biomarker in cancer detection. Finally, it will discuss the potential of using extracellular miRNAs in different cancer diagnoses and challenges associated with the clinical application of extracellular miRNAs as noninvasive biomarkers.


Asunto(s)
Biomarcadores de Tumor/genética , MicroARN Circulante/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/diagnóstico , Neoplasias/genética , ARN Neoplásico/genética , Biomarcadores de Tumor/sangre , MicroARN Circulante/sangre , Detección Precóz del Cáncer/métodos , Exosomas/química , Femenino , Humanos , Masculino , Neoplasias/sangre , Neoplasias/patología , Especificidad de Órganos , Pronóstico , ARN Neoplásico/sangre
5.
Orv Hetil ; 161(11): 403-412, 2020 Mar.
Artículo en Húngaro | MEDLINE | ID: mdl-32148095

RESUMEN

One of the most remarkable chapters in recent years' research of molecular biology is the quest for non-coding ribonucleic acids (RNAs). Circular RNAs form a distinct group within non-coding RNAs and their significance is being discovered only now. These uncommonly stable molecules take part in the regulation of gene expression by various mechanisms, e.g., by decoying microRNAs or by acting upon the translational machinery. The altered expression of circular RNAs was described in different types of cancers, and considering their stability, circular RNAs could be exploited as future biomarkers and even as molecular targets. In this synopsis, the authors present the biological characteristics and the tumor-biological relevance of circular RNAs. Orv Hetil. 2020; 161(11): 403-412.


Asunto(s)
MicroARNs/genética , Neoplasias/genética , ARN Neoplásico , Biomarcadores de Tumor , Humanos , MicroARNs/metabolismo , ARN no Traducido
6.
BMC Bioinformatics ; 21(1): 45, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-32024475

RESUMEN

BACKGROUND: Current popular variant calling pipelines rely on the mapping coordinates of each input read to a reference genome in order to detect variants. Since reads deriving from variant loci that diverge in sequence substantially from the reference are often assigned incorrect mapping coordinates, variant calling pipelines that rely on mapping coordinates can exhibit reduced sensitivity. RESULTS: In this work we present GeDi, a suffix array-based somatic single nucleotide variant (SNV) calling algorithm that does not rely on read mapping coordinates to detect SNVs and is therefore capable of reference-free and mapping-free SNV detection. GeDi executes with practical runtime and memory resource requirements, is capable of SNV detection at very low allele frequency (<1%), and detects SNVs with high sensitivity at complex variant loci, dramatically outperforming MuTect, a well-established pipeline. CONCLUSION: By designing novel suffix-array based SNV calling methods, we have developed a practical SNV calling software, GeDi, that can characterise SNVs at complex variant loci and at low allele frequency thus increasing the repertoire of detectable SNVs in tumour genomes. We expect GeDi to find use cases in targeted-deep sequencing analysis, and to serve as a replacement and improvement over previous suffix-array based SNV calling methods.


Asunto(s)
Variación Genética , Genoma , Neoplasias/genética , Programas Informáticos , Algoritmos , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación Completa del Genoma
7.
Gene ; 736: 144415, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32006598

RESUMEN

In recent days, RNA modifications are gaining the interest of biologist worldwide. Till date, a total of 171 RNA modifications has been reported, and the number may increase with advancing technologies. The mRNA undergoes modifications like m5M, hm5C, m1A, m6A and pseudouridine, collectively called as epitranscriptomic alterations, each of them has their functional significance. m6A modification is the most common one which occurs at the motif of RRm6AACH in mRNA. The altered profiles of these epitranscriptomic changes are reported in multiple cancers. The present review discusses the dynamic nature of functional enzymes called methyltransferase (writer), demethylase (erasers) and m6A binding proteins (readers) and importance of the balance between these proteins for the homeostasis of our body functions like metabolism, circadian rhythm, immune response, viral replications, embryogenesis and cancer development. Nevertheless, the main focus has been on cancer development and progression. The understanding of such differential modifications are at infancy and may provide bring about a paradigm shift in our understanding of cancer for management and treatment.


Asunto(s)
Neoplasias/genética , ARN Mensajero/genética , Progresión de la Enfermedad , Homeostasis/genética , Humanos , Metilación , Neoplasias/patología , Transcriptoma/genética
8.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(1): 19-26, 2020 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-32096373

RESUMEN

Recent studies showed that certain drugs can change regulatory reaction parameters in gene regulatory networks (GRNs) and therefore restore pathological cells to a normal state. A state control framework for regulating biological networks has been built based on attractors and bifurcation theory to analyze this phenomenon. However, the control signal is self-developed in this framework, of which the parameter perturbation method can only calculate the state transition time of cells with single control variable. Therefore, an optimal control method based on the dynamic optimization algorithms is proposed for complex biological networks modeled by nonlinear ordinary differential equations (ODEs). In this approach, dynamic optimization problems are constructed based on basic characteristics of the biological networks. Furthermore, using an example of a simple low-dimensional three-node GRN and a complex high-dimensional cancer GRN, MATLAB is utilized to calculate optimal control strategies with either single or multiple control variables. This method aims to achieve accurate and rapid state regulation for biological networks, which can provide a reference for experimental researches and medical treatment.


Asunto(s)
Algoritmos , Redes Reguladoras de Genes , Neoplasias/genética , Humanos
9.
Hum Genet ; 139(4): 421-446, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32020362

RESUMEN

Y chromosome (ChrY), the male-specific sex chromosome, has been considered as a genetic wasteland. Aging-related mosaic loss of ChrY (LOY) has been known for more than half a century, but it was constantly considered as a neutral karyotype related to normal aging. These views have been challenged with genome-wide association studies identifying mosaic LOY in human somatic cells is the most commonly acquired mutation in male's genome and is associated with a wide spectrum of human diseases including cancer, Alzheimer's disease, and cardiovascular disease. These previously undescribed clinical significances deeply modify our perception on ChrY and open up a range of new questions. Here, we review the latest advances in our knowledge of the biological origins and clinical consequences of mosaic LOY. We highlight the association of mosaic LOY to pathogenic conditions and evaluate the cause-and-consequence relationships between mosaic LOY and pathogenesis. The known risk factors of mosaic LOY including age, genetic variants, ChrY structural aberrations and environmental stressors are discussed. In light of evidence from pioneering and more recent studies, we propose the micronucleation hypothesis and centromere-dysfunction and telomere-attrition models to explain how mosaic LOY occurs and why ChrY is prone to lose. We believe it is importantly and timely to extend mosaic LOY research from epidemiological associations to mechanistic studies. In this regard, we outline important gaps and assess several future directions from a biological and clinical perspective. An improved understanding of mosaic LOY will open new pathways to modify and increase healthy aging in males.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Cromosomas Humanos Y , Mosaicismo , Neoplasias , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Cromosomas Humanos Y/genética , Cromosomas Humanos Y/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Neoplasias/genética , Neoplasias/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 200-204, 2020 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-32034755

RESUMEN

Many recent studies have proved that ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important nuclear protein associated with tumorigenesis, which plays a significant role in epigenetic regulation, especially in DNA methylation and histone methylation. For its particular domains, UHRF1 plays a critical role in biological behaviors including cell proliferation, cell cycle, and apoptosis. Overexpression of UHRF1 in various tumors is closely associated with the angiogenesis in tumors. This paper will provide a review of the regulation of UHRF1 in DNA methylation and histone methylation, and discuss the potential epigenetic role of UHRF1 in angiogenesis.


Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Metilación de ADN , Neovascularización Patológica/genética , Ubiquitina-Proteína Ligasas/genética , Epigénesis Genética , Humanos , Neoplasias/genética , Neoplasias/patología
11.
Adv Exp Med Biol ; 1240: 25-33, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32060885

RESUMEN

Interleukin (IL)-8 is a chemokine that is essential for inflammation and angiogenesis. IL-8 expression is elevated in tumor cell lines and tissues, as well as in peripheral blood obtained from cancer patients. Primary works have attempted to determine the biological effect of IL-8 on tumor cells, including cell proliferation, survival, and migration. More recently, IL-8 has acquired considerable attention as an immune modulator in the context of certain tumor microenvironments (TME); specifically, it can support a niche that favors tumor progression and metastasis. Tumor-derived IL-8 stimulates inflammation by interacting with the microenvironmental constituents, including fibroblasts, endothelial cells, and immune cells. However, the tumor immune system is complex, and mechanisms that construct the immune phenotype remain incompletely characterized. Herein, we will (1) address a potential role of IL-8 in regulating gene expression to establish immune landscape in tumor. Then, we will (2) review IL-8 signaling in the maintenance of stem cells and regulation of hematopoietic progenitors. Finally, (3) IL-8 functions will be discussed in naturally occurring animal cancers that offer a clinically realistic model for translational research. This chapter will provide a new insight into the tumor immune niche and help us develop immunotherapies for cancers.


Asunto(s)
Interleucina-8/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología , Animales , Humanos , Inmunoterapia , Interleucina-8/metabolismo , Neoplasias/genética , Neoplasias/terapia
12.
Cancer Treat Rev ; 84: 101974, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32014824

RESUMEN

Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.


Asunto(s)
Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Humanos , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética
13.
Nucleic Acids Res ; 48(4): 1764-1778, 2020 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-31965184

RESUMEN

Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.


Asunto(s)
Biomarcadores , Quimera/genética , ARN/genética , Quimera/clasificación , Humanos , Neoplasias/genética , ARN/química , ARN/clasificación
14.
PLoS One ; 15(1): e0221681, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31923208

RESUMEN

DNA repair inhibition has been described as an essential event leading to the initiation of carcinogenesis. In a previous study, we observed that the exposure to metal mixture induces changes in the miR-nome of the cells that was correlated with the sub-expression of mRNA involved in processes and diseases associated with metal exposure. From this analysis, one of the miRNAs that shows changes in its expression is miR-222, which is overexpressed in various cancers associated with exposure to metals. In silico studies showed that a possible target for the microRNA-222 could be Rad 51c, a gene involved in the double-stranded DNA repair. We could appreciate that up-regulation of miR-222 reduces the expression both gene and as a protein expression of Rad51c by RT-PCR and immunoblot, respectively. A luciferase assay was performed to validate Rad51c as miR-222 target. Neutral comet assay was performed in order to evaluate DNA double-strand breaks under experimental conditions. Here, we demonstrate that miR-222 up-regulation, directly regulates Rad51c expression negatively, and impairs homologous recombination of double-strand break DNA repair during the initiation stage of cell transformation. This inhibition triggers morphological transformation in a two-stage Balb/c 3T3 cell assay, suggesting that this small RNA acts as an initiator of the carcinogenesis process.


Asunto(s)
Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/genética , MicroARNs/genética , Neoplasias/genética , Células 3T3 , Animales , Simulación por Computador , ADN/efectos de los fármacos , ADN/genética , Reparación del ADN/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Recombinación Homóloga/efectos de los fármacos , Recombinación Homóloga/genética , Humanos , Metales/metabolismo , Ratones
15.
Nat Commun ; 11(1): 197, 2020 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-31924765

RESUMEN

A number of point mutations have been identified in reprogrammed pluripotent stem cells such as iPSCs and ntESCs. The molecular basis for these mutations has remained elusive however, which is a considerable impediment to their potential medical application. Here we report a specific stage at which iPSC generation is not reduced in response to ionizing radiation, i.e. radio-resistance. Quite intriguingly, a G1/S cell cycle checkpoint deficiency occurs in a transient fashion at the initial stage of the genome reprogramming process. These cancer-like phenomena, i.e. a cell cycle checkpoint deficiency resulting in the accumulation of point mutations, suggest a common developmental pathway between iPSC generation and tumorigenesis. This notion is supported by the identification of specific cancer mutational signatures in these cells. We describe efficient generation of human integration-free iPSCs using erythroblast cells, which have only a small number of point mutations and INDELs, none of which are in coding regions.


Asunto(s)
Puntos de Control de la Fase G1 del Ciclo Celular/genética , Células Madre Pluripotentes Inducidas/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/genética , Animales , División Celular , Reprogramación Celular , Eritroblastos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de la radiación , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de la radiación , Neoplasias/genética , Sistemas de Lectura Abierta , Mutación Puntual , Puntos de Control de la Fase S del Ciclo Celular/efectos de la radiación , Rayos X
16.
Nucleic Acids Res ; 48(3): 1192-1205, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31950163

RESUMEN

Somatic synonymous mutations are one of the most frequent genetic variants occurring in the coding region of cancer genomes, while their contributions to cancer development remain largely unknown. To assess whether synonymous mutations involved in post-transcriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types. By employing our developed algorithm, PIVar, we identified a total of 22,948 posttranscriptionally impaired synonymous SNVs (pisSNVs) spanning 2,042 genes. In addition, 35 RNA binding proteins impacted by these identified pisSNVs were significantly enriched. Remarkably, we discovered markedly elevated ratio of somatic pisSNVs across all 22 cancer types, and a high pisSNV ratio was associated with worse patient survival in five cancer types. Intriguing, several well-established cancer genes, including PTEN, RB1 and PIK3CA, appeared to contribute to tumorigenesis at both protein function and posttranscriptional regulation levels, whereas some pisSNV-hosted genes, including UBR4, EP400 and INTS1, exerted their function during carcinogenesis mainly via posttranscriptional mechanisms. Moreover, we predicted three drugs associated with two pisSNVs, and numerous compounds associated with expression signature of pisSNV-hosted genes. Our study reveals the prevalence and clinical relevance of pisSNVs in cancers, and emphasizes the importance of considering posttranscriptional impaired synonymous mutations in cancer biology.


Asunto(s)
Carcinogénesis/genética , Genoma Humano/genética , Neoplasias/genética , Mutación Silenciosa/genética , Adulto , Anciano , Proteínas de Unión a Calmodulina/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Exoma/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/clasificación , Neoplasias/patología , Fosfohidrolasa PTEN/genética , Supervivencia sin Progresión , Procesamiento Proteico-Postraduccional/genética , Sitios de Carácter Cuantitativo/genética , Proteínas de Unión a Retinoblastoma/genética , Ubiquitina-Proteína Ligasas/genética , Proteína Wnt1/genética
17.
Cancer Sci ; 111(3): 774-782, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31955490

RESUMEN

The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss-of-function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Cromatina/genética , Neoplasias/genética , Humanos , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Medicina de Precisión/métodos
18.
BMC Bioinformatics ; 21(1): 7, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31906867

RESUMEN

BACKGROUND: Non-negative matrix factorization (NMF) is a technique widely used in various fields, including artificial intelligence (AI), signal processing and bioinformatics. However existing algorithms and R packages cannot be applied to large matrices due to their slow convergence or to matrices with missing entries. Besides, most NMF research focuses only on blind decompositions: decomposition without utilizing prior knowledge. Finally, the lack of well-validated methodology for choosing the rank hyperparameters also raises concern on derived results. RESULTS: We adopt the idea of sequential coordinate-wise descent to NMF to increase the convergence rate. We demonstrate that NMF can handle missing values naturally and this property leads to a novel method to determine the rank hyperparameter. Further, we demonstrate some novel applications of NMF and show how to use masking to inject prior knowledge and desirable properties to achieve a more meaningful decomposition. CONCLUSIONS: We show through complexity analysis and experiments that our implementation converges faster than well-known methods. We also show that using NMF for tumour content deconvolution can achieve results similar to existing methods like ISOpure. Our proposed missing value imputation is more accurate than conventional methods like multiple imputation and comparable to missForest while achieving significantly better computational efficiency. Finally, we argue that the suggested rank tuning method based on missing value imputation is theoretically superior to existing methods. All algorithms are implemented in the R package NNLM, which is freely available on CRAN and Github.


Asunto(s)
Biología Computacional/métodos , Neoplasias/genética , Algoritmos , Humanos
19.
BMC Bioinformatics ; 21(1): 16, 2020 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-31931698

RESUMEN

BACKGROUND: Cell-type heterogeneity of tumors is a key factor in tumor progression and response to chemotherapy. Tumor cell-type heterogeneity, defined as the proportion of the various cell-types in a tumor, can be inferred from DNA methylation of surgical specimens. However, confounding factors known to associate with methylation values, such as age and sex, complicate accurate inference of cell-type proportions. While reference-free algorithms have been developed to infer cell-type proportions from DNA methylation, a comparative evaluation of the performance of these methods is still lacking. RESULTS: Here we use simulations to evaluate several computational pipelines based on the software packages MeDeCom, EDec, and RefFreeEWAS. We identify that accounting for confounders, feature selection, and the choice of the number of estimated cell types are critical steps for inferring cell-type proportions. We find that removal of methylation probes which are correlated with confounder variables reduces the error of inference by 30-35%, and that selection of cell-type informative probes has similar effect. We show that Cattell's rule based on the scree plot is a powerful tool to determine the number of cell-types. Once the pre-processing steps are achieved, the three deconvolution methods provide comparable results. We observe that all the algorithms' performance improves when inter-sample variation of cell-type proportions is large or when the number of available samples is large. We find that under specific circumstances the methods are sensitive to the initialization method, suggesting that averaging different solutions or optimizing initialization is an avenue for future research. CONCLUSION: Based on the lessons learned, to facilitate pipeline validation and catalyze further pipeline improvement by the community, we develop a benchmark pipeline for inference of cell-type proportions and implement it in the R package medepir.


Asunto(s)
Biología Computacional/normas , Metilación de ADN , Neoplasias/genética , Algoritmos , Biología Computacional/métodos , Simulación por Computador , Humanos , Programas Informáticos
20.
Nat Commun ; 11(1): 69, 2020 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900418

RESUMEN

Cancer driver gene alterations influence cancer development, occurring in oncogenes, tumor suppressors, and dual role genes. Discovering dual role cancer genes is difficult because of their elusive context-dependent behavior. We define oncogenic mediators as genes controlling biological processes. With them, we classify cancer driver genes, unveiling their roles in cancer mechanisms. To this end, we present Moonlight, a tool that incorporates multiple -omics data to identify critical cancer driver genes. With Moonlight, we analyze 8000+ tumor samples from 18 cancer types, discovering 3310 oncogenic mediators, 151 having dual roles. By incorporating additional data (amplification, mutation, DNA methylation, chromatin accessibility), we reveal 1000+ cancer driver genes, corroborating known molecular mechanisms. Additionally, we confirm critical cancer driver genes by analysing cell-line datasets. We discover inactivation of tumor suppressors in intron regions and that tissue type and subtype indicate dual role status. These findings help explain tumor heterogeneity and could guide therapeutic decisions.


Asunto(s)
Biología Computacional/métodos , Genes Supresores de Tumor , Neoplasias/genética , Oncogenes , Metilación de ADN , Humanos , Mutación , Programas Informáticos
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