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Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in human cancers due to mutation, amplification, and epigenetic hyperactivity, which leads to deregulated transcriptional mechanism. Among the eight different EGFR isoforms, the mechanism of regulation of full-length variant 1 is well-known, no studies have examined the function & factors regulating the expression of variant 8. This study aimed to understand the function of EGFR super-enhancer loci and its associated transcription factors regulating the expression of EGFR variant 8. Our study shows that overexpression of variant 8 and its transcription was more prevalent than variant 1 in many cancers and positively correlated with the EGFR-AS1 expression in oral cancer and HNSCC. Notably, individuals overexpressing variant 8 showed shorter overall survival and had a greater connection with other clinical traits than patients with overexpression of variant 1. In this study, TCGA enhancer RNA profiling on the constituent enhancer (CE1 and CE2) region revealed that the multiple enhancer RNAs formed from CE2 by employing CE1 as a promoter. Our bioinformatic analysis further supports the enrichment of enhancer RNA specific chromatin marks H3K27ac, H3K4me1, POL2 and H2AZ on CE2. GeneHancer and 3D chromatin capture analysis showed clustered interactions between CE1, CE2 loci and this interaction may regulates expression of both EGFR-eRNA and variant 8. Moreover, increased expression of SNAI2 and its close relationship to EGFR-AS1 and variant 8 suggest that SNAI2 could regulates variant 8 overexpression by building a MegaTrans complex with both EGFR-eRNA and EGFR-AS1. Our findings show that EGFR variant 8 and its transcriptional regulation & chromatin modification by eRNAs may provide a rationale for targeting RNA splicing in combination with targeted EGFR therapies in cancer.
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ARN Potenciadores , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Súper Potenciadores , Receptores ErbB/genética , Cromatina/genética , Neoplasias de Cabeza y Cuello/genéticaRESUMEN
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that gets inputs from the amino acids, nutrients, growth factor, and environmental cues to regulate varieties of fundamental cellular processes which include protein synthesis, growth, metabolism, aging, regeneration, autophagy, etc. The mTOR is frequently deregulated in human cancer and activating somatic mutations of mTOR were recently identified in several types of human cancer and hence mTOR is therapeutically targeted. mTOR inhibitors were commonly used as immunosuppressors and currently, it is approved for the treatment of human malignancies. This review briefly focuses on the structure and biological functions of mTOR. It extensively discusses the genetic deregulation of mTOR including amplifications and somatic mutations, mTOR-mediated cell growth promoting signaling, therapeutic targeting of mTOR and the mechanisms of resistance, the role of mTOR in precision medicine and other recent advances in further understanding the role of mTOR in cancer.
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Susceptibilidad a Enfermedades , Neoplasias/etiología , Neoplasias/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Biomarcadores de Tumor , Resistencia a Antineoplásicos/genética , Activación Enzimática , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Terapia Molecular Dirigida , Mutación , Tasa de Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Ras proteins play a crucial role as a central component of the cellular networks controlling a variety of signaling pathways that regulate growth, proliferation, survival, differentiation, adhesion, cytoskeletal rearrangements and motility of a cell. Almost, 4 decades passed since Ras research was started and ras genes were originally discovered as retroviral oncogenes. Later on, mutations of the human RAS genes were linked to tumorigenesis. Genetic analyses found that RAS is one of the most deregulated oncogenes in human cancers. In this review, we summarize the pioneering works which allowed the discovery of RAS oncogenes, the finding of frequent mutations of RAS in various human cancers, the role of these mutations in tumorigenesis and mutation-activated signaling networks. We further describe the importance of RAS mutations in personalized or precision medicine particularly in molecular targeted therapy, as well as their use as diagnostic and prognostic markers as therapeutic determinants in human cancers.
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Genes ras , Predisposición Genética a la Enfermedad , Mutación , Neoplasias/genética , Alelos , Biomarcadores de Tumor , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética/métodos , Humanos , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisión/métodos , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Oral squamous cell carcinoma (OSCC) of the head and neck is one of the six most common cancers in the world. OSCC remains the most common cause of cancer deaths in Asian countries. Conventional treatments for OSCC have not improved the overall 5 years survival and therefore alternative therapeutic targets are often sought. Ras is one of the most frequently deregulated oncogenes in oral cancer. Direct targeting the ras has proven unrealistic and hence, exploring and understanding alternative pathways and/or molecules which regulate ras and its signaling that could pave the way for novel molecular targets and therapy for oral cancer. Recently, microRNAs (miRNAs) have been reported to regulate ras oncogenes in human cancers. In this article, we address the microRNA-mediated regulation of the ras oncogenes in oral cancer. We describe extensively the tumor suppressive and oncogenic roles of miRNAs in regulation of ras oncogenes in OSCC. We also discuss the role of miRNA-mediated ras regulation in therapeutic determination of oral cancer. Complete understanding of the miRNA regulation of ras oncogenes in oral cancer may facilitate to plan better strategies for diagnosis, molecular therapeutic targeting and the overall prognosis of this common and deadly cancer.
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Carcinoma de Células Escamosas/genética , MicroARNs/genética , Neoplasias de la Boca/genética , Proteína Oncogénica p21(ras)/genética , Carcinoma de Células Escamosas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/metabolismo , Neoplasias de la Boca/patología , Proteína Oncogénica p21(ras)/biosíntesis , Pronóstico , Transducción de SeñalRESUMEN
BACKGROUND: BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). Previous studies on DTC have well documented high rates of the BRAF (V600E) mutation in patients of mixed ages. Previous studies either included a mix of pediatric and adult patients or pediatric patients only. However, the prevalence of hotspot and non-hotspot BRAF mutations and its significance in pure adult DTCs is not yet well determined. In this study we determine the frequency of this classical BRAF mutation and other rare BRAF mutations in pure adult DTCs. METHODS: A total of 204 adult DTC samples (Age >18 years) were analyzed for mutations in exon 15 of the BRAF gene by performing polymerase chain reaction (PCR) amplification of tumor genomic DNAs and direct sequencing of amplicons using Sanger sequencing. Obtained results were correlated to clinical and pathological characteristics of DTCs. Statistical analyses were performed using SPSS (The Statistical Package for Social Sciences) version 20 software. RESULTS: Overall, BRAF mutations were identified in 48.5 % (99/204) of adult DTCs. Three rare non-hotspot mutations (T599I, T599dup and K601E) were detected in four tumor samples (2 %). One (K601E) of these non-hotspot mutations occurred in conventional papillary thyroid cancer (CPTC) and other three (T599I, T599dup and K601E) were found in follicular variant PTC. We found significant association between BRAF (V600E) mutation and age (P < 0.0001), extrathyroidal invasion (P = 0.017), lymph node metastasis (P = 0.038) and TNM stage III/IV (P = 0.001). CONCLUSIONS: Our study is the first to report BRAF mutations in a pure adult sample of DTCs of Saudi Arabian ethnicity. Our results show a high rate and a strong prognostic role of the classical BRAF (V600E) mutation and also suggest a common occurrence of non-hot spot mutations in adult DTC from this highly inbred population.
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Diferenciación Celular/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Adulto , Anciano , Secuencia de Bases , Exones/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Squamous cell carcinoma (SCC) of the uterine cervix and oral cavity are most common cancers in India. Telomerase reverse transcriptase (TERT) overexpression is one of the hallmarks for cancer, and activation through promoter mutation C228T and C250T has been reported in variety of tumors and often shown to be associated with aggressive tumors. In the present study, we analyzed these two hot spot mutations in 181 primary tumors of the uterine cervix and oral cavity by direct DNA sequencing and correlated with patient's clinicopathological characteristics. We found relatively high frequency of TERT hot spot mutations in both cervical [21.4 % (30/140)] and oral [31.7 % (13/41)] squamous cell carcinomas. In cervical cancer, TERT promoter mutations were more prevalent (25 %) in human papilloma virus (HPV)-negative cases compared to HPV-positive cases (20.6 %), and both TERT promoter mutation and HPV infection were more commonly observed in advanced stage tumors (77 %). Similarly, the poor and moderately differentiated tumors of the uterine cervix had both the TERT hot spot mutations and HPV (16 and 18) at higher frequency (95.7 %). Interestingly, we observed eight homozygous mutations (six 228TT and two 250TT) only in cervical tumors, and all of them were found to be positive for high-risk HPV. To the best of our knowledge, this is the first study from India reporting high prevalence of TERT promoter mutations in primary tumors of the uterine cervix and oral cavity. Our results suggest that TERT reactivation through promoter mutation either alone or in association with the HPV oncogenes (E6 and E7) could play an important role in the carcinogenesis of cervical and oral cancers.
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Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de la Boca/genética , Telomerasa/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Mutación , Papillomaviridae/genética , Regiones Promotoras Genéticas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virologíaRESUMEN
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates cell growth, proliferation, and survival. mTOR is frequently activated in human cancers and is a commonly sought anticancer therapeutic target. However, whether the human mTOR gene itself is a proto-oncogene possessing tumorigenicity has not been firmly established. To answer this question, we mutated evolutionarily conserved amino acids, generated eight mutants in the HEAT repeats (M938T) and the FAT (W1456R and G1479N) and kinase (P2273S, V2284M, V2291I, T2294I, and E2288K) domains of mTOR, and studied their oncogenicity. On transient expression in HEK293T cells, these mTOR mutants displayed elevated protein kinase activities accompanied by activated mTOR/p70S6K signaling at varying levels, demonstrating the gain of function of the mTOR gene with these mutations. We selected P2273S and E2288K, the two most catalytically active mutants, to further examine their oncogenicity and tumorigenicity. Stable expression of the two mTOR mutants in NIH3T3 cells strongly activated mTOR/p70S6K signaling, induced cell transformation and invasion, and remarkably, caused rapid tumor formation and growth in athymic nude mice after subcutaneous inoculation of the transfected cells. This study confirms the oncogenic potential of mTOR suggested previously and demonstrates for the first time its tumorigenicity. Thus, beyond the pivotal position of mTOR to relay the oncogenic signals from the upstream phosphatidylinositol 3-kinase/Akt pathway in human cancer, mTOR is capable potentially of playing a direct role in human tumorigenesis if mutated. These results also further support the conclusion that mTOR is a major therapeutic target in human cancers.
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Transformación Celular Neoplásica/metabolismo , Mutación Missense , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Sustitución de Aminoácidos , Animales , Línea Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Estructura Terciaria de Proteína , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/genética , Trasplante HeterólogoRESUMEN
PURPOSE: Long noncoding RNAs (lncRNAs) play an essential role in the epigenetic regulation of various key genes involved in vital cellular functions. A somatic dinucleotide mutation in the lncRNA GAS8-AS1 was reported in Chinese papillary thyroid cancer. However, GAS8-AS1 dinucleotide alteration and its impact have never been explored in differentiated thyroid cancers and other populations. METHODS: We extracted genomic DNA from 265 DTCs and 97 normal healthy subjects, PCR amplified and Sanger sequenced to examine the GAS8-AS1 dinucleotide alteration. Calculated genotype/allele frequency to test Hardy-Weinberg Equilibrium (HWE) and performed a genetic model of inheritance to determine its association with DTC risk. Correlated the GAS8-AS1 dinucleotide variant distribution with clinical characteristics to find the association. Predicted GAS8-AS1 RNA secondary structure for wild type and variant using RemuRNA and RNAfold to assess the conformational changes. RESULTS: GAS8-AS1 dinucleotide alteration (n.713A > G, rs55742939; n.714T > C, rs61118444) identified in DTCs is a germline variant not somatic. The GAS8-AS1 genotype and allele frequency significantly deviated for HWE in DTCs (χ2 = 37.954; p = 0.0001) though not associated with its risk. Dinucleotide variant distribution was remarkably associated with early-stage disease (p = 0.002), lymph node (p = 0.01), and distant metastasis (p = 0.01) in DTCs. The GAS8-AS1 bearing dinucleotide variant markedly showed conformational change compared to that of its wild type. CONCLUSIONS: These findings indicate that GAS8-AS1 is genetically deregulated and implicated in several stages of DTC tumorigenesis suggesting it could be a promising prognostic biomarker in DTCs.
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Metástasis Linfática , ARN Largo no Codificante , Neoplasias de la Tiroides , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Metástasis Linfática/genética , Estadificación de Neoplasias , ARN Largo no Codificante/genética , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection affects several important organs including endocrine glands. Experimental studies demonstrated that the virus exploits the ACE2, a transmembrane glycoprotein on the cell surface as a receptor for cellular entry. This entry process is exclusively facilitated by other intracellular protein molecules such as TMPRSS2, furin, NRP1, and NRP2. Recent findings documented the involvement of the SARS-CoV-2 in inducing various parathyroid disorders including hypoparathyroidism and hypocalcemia, which received significant attention. This review extensively describes rapidly evolving knowledge on the potential part of SARS-CoV-2 in emerging various parathyroid disorders due to SARS-CoV-2 infection particularly parathyroid malfunction in COVID-19 cases, and post-COVID-19 conditions. Further, it presents the expression level of various molecules such as ACE2, TMPRSS2, furin, NRP1, and NRP2 in the parathyroid cells that facilitate the SARS-CoV-2 entry into the cell, and discusses the possible mechanism of parathyroid gland infection. Besides, it explores parathyroid malfunction in COVID-19 vaccine-administered cases. It also explains the possible long-COVID-19 effect on parathyroid and post-COVID-19 management of parathyroid. A complete understanding of the mechanisms of SARS-CoV-2-triggered pathogenesis in parathyroid dysfunctions may curtail treatment options and aid in the management of SARS-CoV-2-infected cases.
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COVID-19 , SARS-CoV-2 , Humanos , Furina/metabolismo , Vacunas contra la COVID-19 , Glándulas Paratiroides/metabolismo , Enzima Convertidora de Angiotensina 2 , Síndrome Post Agudo de COVID-19 , Peptidil-Dipeptidasa ARESUMEN
Context: Multiple tumors in the same patient suggest a genetic predisposition. Here, we report a patient who presented with several unusual types of malignant and benign tumors, presumably due to a pathogenic germline PMS1 mutation. Case: A 69-year-old woman presented with a 2-year history of abdominal pain and diarrhea. A computed tomography scan of the abdomen revealed a gastrointestinal neuroendocrine tumor (GiNET) with liver metastases and a nonfunctional benign adrenal adenoma. Bilateral large lung nodules were thought to be also metastases from the GiNET but turned out to be differentiated thyroid cancer metastases, which later progressed to anaplastic thyroid cancer (ATC) and led to the patient's demise. A right sphenoid wing meningioma causing partial hypopituitarism was diagnosed during her evaluation. A mammogram and a breast ultrasound revealed a 0.3-cm left breast nodule. Due to the multiplicity of her tumors, whole exome sequencing was performed. This revealed a previously described PMS1 deletion mutation causing a frameshift and truncation (NM_000534c.1258delC, p.His420Ilefs*22) but no other pathogenic variant in other cancer genes. DNA isolated from the ATC tumor tissue showed loss of heterozygosity of the same mutation, highly suggestive of its pathogenic role in thyroid cancer and presumably other tumors. Conclusion: This case reports several tumors including thyroid cancer, GiNET, adrenal adenoma, meningioma, and breast nodule, likely due to the PMS1 mutation found in this patient.
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Context: The American Thyroid Association risk stratification (ATA) and the American Joint Committee on Cancer Tumor Node Metastases (TNM) predict recurrence and mortality of differentiated thyroid cancer (DTC). BRAFV600E and TERT promoter mutations have been shown to correlate with the histopathological features and outcome of DTC. Our objectives were to study the correlation of these molecular markers with these clinicopathological-staging systems. Patients and methods: We studied 296 unselected patients, 214 females and 82 males with a median age of 36 years (IQR 23.3-49.0). BRAFV600E and TERT promoter mutations were tested by PCR-based Sanger sequencing. Data were extracted from medical records and analysed using Chi-Square and Fisher Exact tests and Kaplan Meier analysis. Results: Of 296 patients tested, 137 (46.3%) had BRAFV600E-positive tumors and 72 (24.3%) were positive for TERT promoter mutations. The BRAFV600E mutation did not correlate with the ATA and TNM staging, being non-significantly different in various stages of these systems and did not predict the development of persistent disease (PD) (P 0.12). Unlike BRAFV600E, TERT promoter mutations were more frequent in the ATA high-risk than in intermediate- or low-risk tumors (P 0.006) and in TNM stages III and IV than lower stages (P <0.0001). TERT promoter mutations also predicted the outcome, being present in 37.2% of patients with PD compared to only 15.4% in those without evidence of disease (P <0.0001). The same pattern was also seen when BRAFV600E and TERT promoter mutations were combined. Conclusion: TERT promoter mutations alone or in combination with BRAFV600E mutation, but not BRAFV600E mutation alone, correlated well with the ATA and TNM staging and predicted development of PD, especially in higher stages of these systems.
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Adenocarcinoma , Carcinoma Papilar , Telomerasa , Neoplasias de la Tiroides , Masculino , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo/patología , Carcinoma Papilar/patología , Regiones Promotoras Genéticas/genética , Telomerasa/genética , Neoplasias de la Tiroides/patología , Adenocarcinoma/patología , MutaciónRESUMEN
CONTEXT: Diffuse sclerosing papillary thyroid cancer (DSPTC) is rare, with limited data on its molecular genetics. OBJECTIVE: We studied the molecular genetics of a cohort of DSPTC. METHODS: DNA was isolated from paraffin blocks of 22 patients with DSPTC (15 females, 7 males, median age 18 years, range 8-81). We performed polymerase chain reaction-based Sanger sequencing and a next-generation sequencing (NGS) gene panel to characterize the genomic landscape of these tumors. We classified genetic alterations to definitely or probably pathogenic. Definitely pathogenic are genetic alterations that are well known to be associated with PTC (e.g., BRAFV600E). Probably pathogenic are other alterations in genes that were reported in The Cancer Genome Atlas or the poorly differentiated and anaplastic thyroid cancer datasets. RESULTS: Three tumors were tested only by Sanger sequencing and were negative for BRAFV600E, HRAS, KRAS, NRAS, TERT promoter, PTEN, and PIK3CA mutations. The other 19 tumors tested by NGS showed definitely pathogenic alterations in 10 patients (52.6%): 2/19 (10.5%) BRAFV600E, 5/19 (26.3%) CCDC6-RET (RET/PTC1), 1/19 (5.3%) NCOA4-RET (RET/PTC3), 1/19 (5.3%) STRN-ALK fusion, and 2/19 (10.6%) TP53 mutations. Probably pathogenic alterations occurred in 13/19 tumors (68.4%) and included variants in POLE (31.6%), CDKN2A (26%), NF1 (21%), BRCA2 (15.8%), SETD2 (5.3%), ATM (5.3%), FLT3 (5.3%), and ROS1 (5.3%). In 1 patient, the gene panel showed no alterations. No mutations were found in the RAS, PTEN, PIK3CA, or TERT promoter in all patients. There was no clear genotype/phenotype correlation. CONCLUSION: In DSPTC, fusion genes are common, BRAFV600E is rare, and other usual point mutations are absent. Pathogenic and likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3, and ROS1 occur in about two-thirds of DTPTC.
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Neoplasias de la Tiroides , Masculino , Femenino , Humanos , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Biología Molecular , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Purpose: About 40% of paragangliomas (PGL) are due to germline mutations in one of several susceptibility genes. These genes rarely predispose to other non-PGL tumors. Here, we describe and functionally characterize a germline SDHB mutation in a patient who developed a BRAF V600E mutation-positive papillary thyroid cancer (PTC) and a TERT promotor mutation-positive PGL. Experimental design: A 28-year-old asymptomatic man was discovered incidentally to have a large left-sided mid-abdominal PGL and PTC. He underwent resection of the PGL and total thyroidectomy and neck dissection followed by I-131 adjuvant therapy for PTC. The histopathology revealed a high-grade PGL and a tall cell-variant PTC with lymph node metastases (T1b N1b M0). He soon developed PGL spinal metastases that have been rapidly progressing and is currently being treated with Lu177-dotatate therapy. Family screening revealed a positive SDHB mutation in the mother, a son, and a brother. Results: In addition to the heterozygous SDHB germline mutation (c.688C>T, p.Arg230Cys), molecular analysis revealed a somatic TERT promotor mutation (C228T) in PGL (negative in PTC) and a somatic BRAF V600E mutation in PTC (negative in PGL). Functional studies showed a higher proliferation rate in the mutant compared with the wild-type SDHB. Conclusion: Germline SDHB mutations rarely occur in patients with PTC and may contribute to its aggressiveness. Somatic TERT promotor mutations rarely occur in PGL and contribute to its aggressiveness and metastatic potential.
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Glioma is the most common intracranial tumor with poor treatment outcomes and has high morbidity and mortality. Various studies on genomic analyses of glioma found a variety of deregulated genes with somatic mutations including TERT, TP53, IDH1, ATRX, TTN, etc. The genetic alterations in the key genes have been demonstrated to play a crucial role in gliomagenesis by modulating important signaling pathways that alter the fundamental intracellular functions such as DNA damage and repair, cell proliferation, metabolism, growth, wound healing, motility, etc. The SPRK1, MMP2, MMP9, AKT, mTOR, etc., genes, and noncoding RNAs (miRNAs, lncRNAs, circRNAs, etc.) were shown mostly to be implicated in the metastases of glioma. Despite advances in the current treatment strategies, a low-grade glioma is a uniformly fatal disease with overall median survival of â¼ 5-7 years while the patients bearing high-grade tumors display poorer median survival of â¼ 9-10 months mainly due to aggressive metastasis and therapeutic resistance. This review discusses the spectrum of deregulated genes, molecular and cellular mechanisms of metastasis, recurrence, and its management, the plausible causes for the development of therapy resistance, current treatment options, and the recent trends in malignant gliomas. Understanding the pathogenic mechanisms and advances in molecular genetics would aid in the novel diagnosis, prognosis, and translation of pathogenesis-based treatment opportunities which could pave the way for precision medicine in glioma.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Resistencia a Medicamentos , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Mutación , PronósticoRESUMEN
OBJECTIVE: The objective of this study is to identify the association between linc-ROR genetic variants and oral squamous cell carcinoma tumorigenesis. DESIGN: Four genetic variants of linc-ROR (rs6420545, rs4801078, rs1942348, and rs9636089) were analyzed in 178 OSCCs and 191 controls of the South Indian population by PCR amplification followed by restriction digestion. In addition, we examined whether these variants alter linc-ROR expression levels and the progression of OSCC. RESULTS: The frequency of linc-ROR rs6420545 and rs4801078 genotypes were significantly associated with advanced tumor grade (>2) (p = 0.002 and p = 0.048), and nodal metastasis (p = 0.001 and p = 0.019), respectively. We observed a significant association of rs6420545 specifically in the over-dominant model [OR 1.77 (95%CI; 1.17-2.68); p = 0.006] and rs9636089 in dominant model [OR 2.17 (95%CI; 1.06 - 4.46); p = 0.03], and allelic model [OR 2.26 (95%CI; 1.13 - 4.53) p = 0.02], respectively. Further, significant upregulation of linc-ROR (p = 0.005) was observed in our cohort, consistent with the HNSCC TCGA dataset (p < 0.0001). CONCLUSIONS: Our findings suggest that the linc-ROR genetic variants could contribute to the metastasis and progression mainly in the late event of tumorigenesis of OSCCs and these variants could be useful in the precision therapeutic management of this cancer particularly in prognosis.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , ARN Largo no Codificante , Carcinogénesis , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Humanos , Neoplasias de la Boca/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
INTRODUCTION: Cervical cancer is the second most common cancer in India. The phosphatidylinositol-3 kinase (PI3K) signaling is one of the most commonly activated pathways in cancer and comprises key molecules commonly targeted in cancer therapy. This study analyzed six PI3K pathway gene mutations. METHODS: We carried out targeted next-generation sequencing of six PI3K pathway genes (PIK3CA, PIK3R1, PTEN, AKT1, TSC2, and mTOR) in a total of 93 South Indian cervical cancer samples and confirmed them by sanger sequencing. RESULTS: The PI3K pathway gene mutations were observed in 54.8% (51/93) of the tumors and PIK3CA was the most mutated (34.4%, 32/93), followed by TSC2 (18.3%, 17/93), and PIK3R1 (14%, 13/93). The PIK3CA hotspot mutations E542K and E545K observed in this study were likely to disrupt the p110α-p85α interaction that could result in the PI3K pathway activation. We also found a few novel mutations in PIK3R1, PTEN, AKT1, TSC2, and mTOR genes while some of the tumors harbored multiple mutations in the genes of the PI3K pathway. The majority of the tumors were positive for high-risk HPV16/18 (60.7%). CONCLUSIONS: The high incidence of the PI3K pathway gene mutations observed in this study could be exploited for the therapeutic management of cervical cancers.
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Fosfatidilinositol 3-Quinasas , Neoplasias del Cuello Uterino , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 18/metabolismo , Humanos , Incidencia , Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias del Cuello Uterino/genéticaRESUMEN
Coronavirus disease 2019 (COVID-19) advances to affect every part of the globe and remains a challenge to the human race. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was shown to affect many organs and organ systems including the thyroid gland as these parts highly express angiotensin-converting enzyme 2 (ACE2) protein, which functions as a receptor for initially entering the virus into the cells. Furthermore, some categories of the population including older people and persons with comorbidities are prone to be more vulnerable to COVID-19 and its complications. Recent reports showed that SARS-CoV-2 infection could cause Graves' disease (autoimmune hyperthyroidism) in post-COVID-19 patients. Factors that may boost the mortality risk of COVID-19 patients are not completely known yet and a clear perception of the group of vulnerable people is also essential. This review briefly summarizes the features of Graves' disease such as symptoms, risk factors, including environmental, genetic, immunological, and other factors, associated disorders, and therapeutic options. It comprehensively describes the recent advances in SARS-CoV-2-induced Graves' disease and the pivotal role of autoimmune factors in inducing the disease. The review also discusses the possible risks of SARS-CoV-2 infection and associated COVID-19 in people with hyperthyroidism. Furthermore, it explains thyroid disease and its association with the severity of COVID-19.
Asunto(s)
COVID-19 , Enfermedad de Graves , Anciano , Comorbilidad , Enfermedad de Graves/epidemiología , Humanos , Peptidil-Dipeptidasa A , Factores de Riesgo , SARS-CoV-2RESUMEN
Coronavirus disease-2019 (COVID-19) is asymptomatic in most cases, but it is impartible and fatal in fragile and elderly people. Heretofore, more than four million people succumbed to COVID-19, while it spreads to every part of the globe. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) induces various dysfunctions in many vital organs including the thyroid by utilizing ACE2 as a receptor for cellular entry. Emerging reports clearly show the involvement of SARS-CoV-2 in diverse thyroid disorders. Thus, this review article aims to review comprehensively all the recent developments in SARS-CoV-2-induced pathogenesis of thyroid diseases. The review briefly summarizes the recent key findings on the mechanism of SARS-CoV-2 infection, the role of ACE2 receptor in viral entry, SARS-CoV-2-activated molecular signaling in host cells, ACE2 expression in the thyroid, cytokine storm, and its vital role in thyroid dysfunction and long-COVID in relation to thyroid and autoimmunity. Further, it extensively discusses rapidly evolving knowledge on the potential part of SARS-CoV-2 in emerging various thyroid dysfunctions during and post-COVID-19 conditions which include subacute thyroiditis, Graves' diseases, Hashimoto's thyroiditis, thyrotoxicosis, and other recent advances in further discerning the implications of this virus within thyroid dysfunction. Unraveling the pathophysiology of SARS-CoV-2-triggered thyroid dysfunctions may aid pertinent therapeutic options and management of these patients in both during and post-COVID-19 scenarios.