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BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families. RESULTS: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS. CONCLUSION: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.
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Síndrome de Birt-Hogg-Dubé , Neoplasias Renales , Síndrome de Birt-Hogg-Dubé/genética , Femenino , Humanos , Masculino , Simulación del Acoplamiento Molecular , Mutación/genética , Nucleótidos , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
A thickened, white patch - leukoplakia - in the oral cavity is usually benign, but sometimes (in ~9% of individuals) it progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues - leukoplakia, tumour, adjacent normal, and blood - from each of 28 patients suffering from gingivobuccal oral cancer. We performed multiomics analysis of the 112 collected tissues (four tissues per patient from 28 patients) and integrated information on progressive changes in the mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole-exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Nonsynonymous somatic mutations in the CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co-occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favour lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal-instability (arm-level deletions of 19p and q, focal-deletion of DNA-repair pathway genes and NOTCH1, amplification of EGFR) (77%), and increased APOBEC-activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact immune-dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T-cells (56%), depletion of cytotoxic T-cells (68%), and antigen-presenting dendritic cells (72%), with a concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (range: 4-10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias de la Boca , Transcriptoma , Transformación Celular Neoplásica/genética , Exoma , Genómica , Humanos , Leucoplasia/genética , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , MutaciónRESUMEN
The concept of polarity in development, homeostasis and pathological alteration of tissues has emerged as an interesting aspect of the concerned biology. The epithelial cells exhibit apicobasal polarity which is maintained by Crumbs complex located at apical region of tight junction, 'PAR' complex at sub-apical region of tight junction and Scribble complex at adherens junction. Any functional perturbation of these proteins cause alteration of normal epithelial physiology en-route to epithelial pathology. In this maiden scientific exercise, we have tried to explore the association of expression of cell polarity proteins in OPMD and OSCC. Here, we have chosen DLG1 as a representative of polarity protein. RNA was isolated from the tissue samples. Then cDNA was prepared by RTPCR technique. qPCR was performed on cDNA samples. Expression data was analysed on the basis of Ct values. Paired t-test was performed with normalized Ct values of disease and normal tissue to determine whether there was any significant difference in expression between them. The statistical tests were done using SPSS software. Results of this study reflected increase in DLG1 expression in high grade dysplasia. There was no significant alteration in expression of DLG1 in WDSCC where there is formation of cluster of neoplastic cells ultimately producing epithelial islands and keratin pearls. But, in case of MDSCC, when the same neoplastic cells keep on invading with minimal keratin pearl formation, they again gain the mesenchymal character in full potential. And this phenomenon supports the upregulation of DLG1 in MDSCC in our study.
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Pediatric nephrolithiasis (NL) or Kidney stone disease (KSD) is an untethered topic in Asian population. In Western countries, the annual incidence of paediatric NL is around 6-10%. Here, we present data from West Bengal, India, on lower age (LA, 0-20 years) NL and its prevalence for the first time. To discover the mutations associated with KSD, twenty-four (18 + 6) rare LA-NL patients were selected for Whole Exome Sequencing (WES) and Sanger sequencing, respectively. It was found that GRHPR c. 494G>A mutation (MZ826703) is predominant in our study cohort. This specific homozygous mutation is functionally studied for the first time directly from human peripheral mononuclear cell (PBMC) samples. Using expression study with biochemical activity and computational analysis we assumed that the mutation is pathogenic with loss of function. Moreover, three genes, AGXT, HOGA1 and GRHPR with Novel variants known to cause hyperoxaluria were found frequently in the study cohort. Our study analyses the genes and variations that cause LA-NL, as well as the molecular function of the GRHPR mutation, which may serve as a clinical marker in the population of West Bengal, Eastern India.
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Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM-receptor interaction, PI3K-Akt signaling, cytokine-cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes-CD274, CD80, and IDO1-were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.
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One of the most important proteins for COVID-19 pathogenesis in SARS-CoV-2 is the ORF3a which is the largest accessory protein among others coded by the SARS-CoV-2 genome. The major roles of the protein include virulence, infectivity, ion channel activity, morphogenesis, and virus release. The coronavirus, SARS-CoV-2 is mutating rapidly, therefore, critical study of mutations in ORF3a is certainly important from the pathogenic perspective. Here, a sum of 175 non-synonymous mutations in the ORF3a of SARS-CoV-2 were identified from 7194 complete genomes of SARS-CoV-2 available from NCBI database. Effects of these mutations on structural stability, and functions of ORF3a were also studied. Broadly, three different classes of mutations, such as neutral, disease, and mixed (neutral and disease) types of mutations were observed. Consecutive phenomena of mutations in ORF3a protein were studied based on the timeline of detection of the mutations. Considering the amino acid compositions of the ORF3a protein, twenty clusters were detected using the K-means clustering method. The present findings on 175 novel mutations of ORF3a proteins will extend our knowledge on ORF3a, a vital accessory protein in SARS-CoV-2, to enlighten the pathogenicity of this life-threatening virus.
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COVID-19/virología , SARS-CoV-2 , Proteínas Viroporinas , Factores de Virulencia , Bases de Datos Genéticas , Genes Virales , Variación Genética , Humanos , Mutación Missense , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , Relación Estructura-Actividad , Proteínas Viroporinas/química , Proteínas Viroporinas/genética , Factores de Virulencia/química , Factores de Virulencia/genéticaRESUMEN
A total number of 3080 SARS-CoV-2 genomes from all continents are considered from the NCBI database. Every accessory protein ORF6, ORF7b, and ORF10 of SARS-CoV-2 possess a single missense mutation in less than 1.5% of the 3080 genomes. It has now been observed that different non-synonymous mutations occurred in these three accessory proteins. Most of these rare mutations are changing the amino acids such as hydrophilic to hydrophobic, acidic or basic to hydrophobic, and vice versa etc. So these highly conserved proteins might play an essential role in virus pathogenicity. This study opens a question whether it carries some messages about the virus rapid replications, and virulence.
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BACKGROUND: Studies of epigenomic alterations associated with diseases primarily focus on methylation profiles of promoter regions of genes, but not of other genomic regions. In our past work (Das et al. 2019) on patients suffering from gingivo-buccal oral cancer - the most prevalent form of cancer among males in India - we have also focused on promoter methylation changes and resultant impact on transcription profiles. Here, we have investigated alterations in non-promoter (gene-body) methylation profiles and have carried out an integrative analysis of gene-body methylation and transcriptomic data of oral cancer patients. METHODS: Tumor and adjacent normal tissue samples were collected from 40 patients. Data on methylation in the non-promoter (gene-body) regions of genes and transcriptome profiles were generated and analyzed. Because of high dimensionality and highly correlated nature of these data, we have used Random Forest (RF) and other data-analytical methods. RESULTS: Integrative analysis of non-promoter methylation and transcriptome data revealed significant methylation-driven alterations in some genes that also significantly impact on their transcription levels. These changes result in enrichment of the Central Carbon Metabolism (CCM) pathway, primarily by dysregulation of (a) NTRK3, which plays a dual role as an oncogene and a tumor suppressor; (b) SLC7A5 (LAT1) which is a transporter dedicated to essential amino acids, and is overexpressed in cancer cells to meet the increased demand for nutrients that include glucose and essential amino acids; and, (c) EGFR which has been earlier implicated in progression, recurrence, and stemness of oral cancer, but we provide evidence of epigenetic impact on overexpression of this gene for the first time. CONCLUSIONS: In rapidly dividing cancer cells, metabolic reprogramming from normal cells takes place to enable enhanced proliferation. Here, we have identified that among oral cancer patients, genes in the CCM pathway - that plays a fundamental role in metabolic reprogramming - are significantly dysregulated because of perturbation of methylation in non-promoter regions of the genome. This result compliments our previous result that perturbation of promoter methylation results in significant changes in key genes that regulate the feedback process of DNA methylation for the maintenance of normal cell division.
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Biomarcadores de Tumor/metabolismo , Carbono/metabolismo , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Boca/patología , Células Madre Neoplásicas/patología , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/metabolismo , Pronóstico , Regiones Promotoras GenéticasRESUMEN
Envelope (E) protein is one of the structural viroporins (76-109 amino acids long) present in the coronavirus. Sixteen sequentially different E-proteins were observed from a total of 4917 available complete SARS-CoV-2 genomes as on 18th June 2020 in the NCBI database. The missense mutations over the envelope protein across various coronaviruses of the ß-genus were analyzed to know the immediate parental origin of the envelope protein of SARS-CoV-2. The evolutionary origin is also endorsed by the phylogenetic analysis of the envelope proteins comparing sequence homology as well as amino acid conservations.
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Proteínas de la Envoltura de Coronavirus/genética , Coronavirus/genética , Mutación Missense , Animales , Camelus/virología , Gatos , Bovinos , Quirópteros/virología , Infecciones por Coronavirus/virología , Humanos , FilogeniaRESUMEN
The genetic diversity of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) in several countries sums up to worldwide genetic diversity. In this present study, variations in terms of missense mutations among the SARS-CoV2 genomes from 128 Indian patients, as of May 2020, are accounted and thereby some key findings with some hypotheses were made. These mutations across various genes of these genomes show wide genetic variations in sequence and rapid evolution of SARS-CoV2 virus. The presence of unique mutations in the studied SARS-CoV2 genomes may led to their attenuation. Few Genes such as ORF6, ORF10 are free from any mutations in the Indian context of 339 genomes observed as of 14th July 2020. Further, E protein contains only one mutation. This may suggest that designing a therapeutic approach against ORF6, ORF10 and E genes may have a beneficial effect in controlling COVID-19 pandemic especially in India.
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COVID-19/virología , Mutación Missense , SARS-CoV-2/genética , Genoma Viral , Humanos , India , SARS-CoV-2/aislamiento & purificaciónRESUMEN
In the NCBI database, as on June 6, 2020, total number of available complete genome sequences of SARS-CoV2 across the world is 3617. The envelope (E) protein of SARS-CoV2 possesses several non-synonymous mutations over the transmembrane and C-terminus domains in 15 (0.414%) genomes among 3617 SARS-CoV2 genomes, analyzed. More precisely, 10(0.386%) out of 2588 genomes from the USA, 3(0.806%) from Asia, 1 (0.348%) from Europe and 1 (0.274%) from Oceania contained the missense mutations over the E-protein of SARS-CoV2 genomes. The C-terminus motif DLLV has been to DFLV and YLLV in the proteins from QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) respectively, which might affect the binding of this motif with the host protein PALS1.
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COVID-19/virología , Proteínas de la Envoltura de Coronavirus/genética , Proteínas de la Envoltura de Coronavirus/metabolismo , Mutación , SARS-CoV-2/genética , Proteínas de la Envoltura de Coronavirus/química , Genoma Viral , Humanos , Proteínas de la Membrana/metabolismo , Nucleósido-Fosfato Quinasa/metabolismo , SARS-CoV-2/aislamiento & purificaciónRESUMEN
It is hypothesized that same driver gene mutations should be present in both oral leukoplakia and cancer tissues. So, we attempted to find out mutations at one of the driver genes, CASP8, in cancer and adjacent leukoplakia tissues. Patients (n = 27), affected by both of cancer and adjacent leukoplakia, were recruited for the study. Blood and tissue DNA samples were used to identify somatic mutations at CASP8 by next generation sequencing method. In total, 56% (15 out of 27) cancer and 30% (8 out of 27) leukoplakia tissues had CASP8 somatic mutations. In 8 patients, both cancer and adjacent leukoplakia tissues, located within 2-5 cm of tumor sites, had identical somatic mutations. But, in 7 patients, cancer samples had somatic mutations but none of the leukoplakia tissues, located beyond 5cm of tumor sites, had somatic mutations. Mutated allele frequencies at CASP8 were found to be more in cancer compared to adjacent leukoplakia tissues. This study provides mutational evidence that oral cancer might have progressed from previously grown leukoplakia lesion. Leukoplakia tissues, located beyond 5cm of cancer sites, were free from mutation. The study implies that CASP8 mutation could be one of the signatures for some of the leukoplakia to progress to oral cancer.
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Caspasa 8/genética , Leucoplasia Bucal/genética , Neoplasias de la Boca/genética , Mutación , Adulto , Anciano , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Humanos , India , Leucoplasia Bucal/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patologíaRESUMEN
BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS: Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS: Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION: Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.
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Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Proteína p53 Supresora de Tumor/genética , Alelos , Ampolla Hepatopancreática/patología , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/diagnóstico , Femenino , Genotipo , Mutación de Línea Germinal , Humanos , Estimación de Kaplan-Meier , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Pancreáticas/diagnóstico , Pronóstico , Neoplasias PancreáticasRESUMEN
BACKGROUND: Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. Although genomic drivers of OSCC-GB have been identified by whole exome and whole genome sequencing, no epigenome-wide study has been conducted in OSCC-GB; our study has filled this gap, and has discovered and validated epigenomic hallmarks of gingivobuccal oral cancer. METHODS: We have carried out integrative analysis of epigenomic (n = 87) and transcriptomic (n = 72) profiles of paired tumor-normal tissues collected from OSCC-GB patients from India. Genome-wide DNA methylation assays and RNA-sequencing were performed on high-throughput platforms (Illumina) using a half-sample of randomly selected patients to discover significantly differentially methylated probes (DMPs), which were validated on the remaining half-sample of patients. RESULTS: About 200 genes showed significant inverse correlation between promoter methylation and expression, of which the most significant genes included genes that act as transcription factors and genes associated with other cancer types. Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation. CONCLUSIONS: In OSCC-GB patients, there are significant alterations in expression of key genes that (a) regulate normal cell division by maintenance of balanced DNA methylation and transcription process, (b) maintain normal physiological signaling (PPAR, B cell receptor) and metabolism (arachidonic acid) pathways, and (c) provide immune protection against antigens, including tumor cells. These findings indicate novel therapeutic targets, including immunotherapeutic, for treatment of OSCC-GB.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Epigenómica/métodos , Redes Reguladoras de Genes , Neoplasias de la Boca/genética , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , India , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Análisis de Secuencia de ARN , Escape del Tumor , Secuenciación Completa del GenomaRESUMEN
AIM: The methylome associated with miRNA loci was investigated in oral cancer to explore tobacco specific methylation and potential biomarkers for patient survival. METHODS: Methylome data was generated from 16 pairs of cancer-normal tissues by reduced representation bisulfite sequencing method. Differentially methylated regions were identified using the DMAP pipeline. In silico validation and Kaplan-Meier survival analyses were performed on The Cancer Genome Atlas data based on our miRNA methylome data. RESULTS: A total of 4310 unique differentially methylated regions, mapping to 144 miRNA loci, were identified. Three distinct groups of miRNAs were differentially methylated in cancer tissues from smokers, chewers and mixed habitués. Hypermethylation of miR-503, miR-200a/b, miR-320b and miR-489 was associated with worse 5-year survival. CONCLUSION: Differential methylation patterns in miRNA loci are associated with poor survival underscoring their potential as predictive and prognostic biomarkers in oral cancer.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , MicroARNs/metabolismo , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Islas de CpG , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Biblioteca de Genes , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/mortalidad , Polimorfismo de Nucleótido Simple , Fumar , Sitio de Iniciación de la TranscripciónRESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) is a complication of chronic obstructive pulmonary disease (COPD) in advance stages, and its presence indicates poor prognosis. AIMS AND OBJECTIVE: The present study was design to know the prevalence of PAH in patients with COPD and its correlation with stages of COPD, exercising capacity, and quality of life. MATERIALS AND METHODS: It is a cross-sectional prevalence study over a period of 1 year from August 2015 to July 2016. The study included 109 COPD patients, diagnosed by spirometry, and severity was determined according Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification criteria. Screening two-dimensional echocardiography was done to determine pulmonary arterial hypertension and exercising capacity assessed by 6 min walk test (6MWT) while the quality of life was assessed by St George respiratory Questionnaire for COPD (SGRQ-C) Questionnaires. RESULTS: Out of 109 patients, PAH was present in 68 (62.4%) cases consisting of mild grade 41 (37.6%), moderate grade 11 (10.1%), and severe grade 16 (14.7%). In GOLD A stage, there were 20 cases of mild PAH and Stage B included 18 cases of mild and 3 cases of moderate PAH. Stage C had 3 cases of mild and 8 cases of moderate PAH while Stage D had 16 cases of severe PAH. In 6MWT, patients with severe grade PAH fail to perform the test while patients with mild to moderate PAH walked short distance. In SGRQ-C Questionnaires symptom, activity, impact, and total score were high with the severity of PAH. CONCLUSION: The prevalence of PAH in COPD was significant. Therefore, every COPD patient should be evaluated for PAH.
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BACKGROUND: Gingivo-buccal squamous cell carcinoma (GBSCC) is one of the most common oral cavity cancers in India with less than 50% patients surviving past 5 years. Here, we report a whole transcriptome profile on a batch of GBSCC tumours with diverse tobacco usage habits. The study provides an entire landscape of altered expression with an emphasis on searching for targets with therapeutic potential. METHODS: Whole transcriptomes of 12 GBSCC tumours and adjacent normal tissues were sequenced and analysed to explore differential expression of genes. Expression changes were further compared with those in TCGA head and neck cohort (n = 263) data base and validated in an independent set of 10GBSCC samples. RESULTS: Differentially expressed genes (n = 2176) were used to cluster the patients based on their tobacco habits, resulting in 3 subgroups. Immune response was observed to be significantly aberrant, along with cell adhesion and lipid metabolism processes. Different modes of immune evasion were seen across 12 tumours with up-regulation or consistent expression of CD47, unlike other immune evasion genes such as PDL1, FUT4, CTLA4 and BTLA which were downregulated in a few samples. Variation in infiltrating immune cell signatures across tumours also indicates heterogeneity in immune evasion strategies. A few actionable genes such as ITGA4, TGFB1 and PTGS1/COX1 were over expressed in most samples. CONCLUSION: This study found expression deregulation of key immune evasion genes, such as CD47 and PDL1, and reasserts their potential as effective immunotherapeutic targets for GBSCC, which requires further clinical studies. Present findings reiterate the idea of using transcriptome profiling to guide precision therapeutic strategies.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Neoplasias de la Boca/genética , Neoplasias de la Boca/inmunología , Transcriptoma/genética , Carcinoma de Células Escamosas/terapia , Ciclo Celular/genética , Ciclo Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunoterapia , India , Masculino , MicroARNs , Neoplasias de la Boca/terapiaRESUMEN
OBJECTIVE: Growth retardation-alopecia-pseudoanodontia-optic atrophy (GAPO) syndrome (Online Mendelian Inheritance in Man [OMIM] ID 230740) is one of the rarest autosomal recessive syndromes. It is characterized by many phenotypes, including wide anterior fontanel, frontal bossing of the face, depressed nasal bridge, along with the 4 classic phenotypes contained in the name of the syndrome. Recent reports identified nonsense, missense, and splicing mutations at different exons of ANTXR1 responsible for GAPO syndrome in patients from different ethnic populations. Here, we are reporting a mutation at ANTXR1 in an Indian patient with GAPO syndrome. STUDY DESIGN: We describe an inherited mutation at ANTXR1 in a 6-year-old Indian boy with GAPO syndrome. RESULTS: Genomic DNA from the patient with the GAPO syndrome and his family members were screened for previously reported mutations at ANTXR1 by sequencing. Novel homozygous and heterozygous mutations in exon-3 of ANTXR1 (c.265 G > A, p.Gly89 Arg) were identified in the patient and in other members of the family, respectively. However, no mutated allele was identified in genomic DNA from unrelated healthy individuals. Bioinformatic analysis by different tools predicted the deleterious, damaging, or aberrant splicing effect of mutation on the protein. CONCLUSIONS: Functional inefficiency of ANTXR1 as a result of mutation might have led to GAPO syndrome.
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Alopecia/genética , Anodoncia/genética , Trastornos del Crecimiento/genética , Mutación/genética , Proteínas de Neoplasias/genética , Atrofias Ópticas Hereditarias/genética , Receptores de Superficie Celular/genética , Niño , Humanos , India , Masculino , Proteínas de Microfilamentos , FenotipoRESUMEN
Mitochondria being the central organelle for metabolism and other cell signalling pathways have remained the topic of interest to tumour biologists. In spite of the wide acceptance of Warburg's hypothesis, role of mitochondrial metabolism in cancer is still unclear. Uncontrolled growth and proliferation, hallmarks of tumour cells, are maintained when the cells adapt to metabolic reprogramming with the help of altered metabolism of mitochondria. This review has focussed on different aspects of mitochondrial metabolism and inter-related signalling pathways which have been found to be modified in cancer.
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Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions.