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1.
Int J Mol Sci ; 19(3)2018 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-29495389

RESUMEN

Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR:NIS interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits NIS. Inhibition of miR-146a-3p restores the expression and function of NIS, increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, p = 0.006). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, p < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, p < 0.001), lack of extrathyroidal invasion (HR = 9.03, p = 0.02), lack of nodular invasion (HR = 7.84, p = 0.002), lack of metastases (HR = 6.5, p = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, p = 0.002). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism.


Asunto(s)
Alelos , Carcinoma Papilar/genética , Carcinoma Papilar/mortalidad , Variación Genética , MicroARNs/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/mortalidad , Regiones no Traducidas 3' , Adulto , Anciano , Carcinoma Papilar/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Pronóstico , Interferencia de ARN , Simportadores/genética , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/patología
2.
Blood Press ; 26(1): 2-8, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27177042

RESUMEN

Multiple factors underlie the pathophysiology of hypertension, involving endothelial dysregulation, vascular smooth muscle dysfunction, increased oxidative stress, sympathetic nervous system activation and altered renin -angiotensin -aldosterone regulatory activity. A class of non-coding RNA called microRNA, consisting of 17-25 nucleotides, exert regulatory function over these processes. This paper summarizes the currently available data from preclinical and clinical studies on miRNA in the development of hypertension as well as the impact of anti-hypertensive treatment on their plasma expression. We present microRNAs' characteristics, their biogenesis and role in the regulation of blood pressure together with their potential diagnostic and therapeutic application in clinical practice.


Asunto(s)
Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipertensión/terapia , MicroARNs/metabolismo , Sistema Renina-Angiotensina , Animales , Humanos
3.
Genes Chromosomes Cancer ; 53(6): 516-23, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24599715

RESUMEN

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína BRCA1/genética , Carcinoma/genética , Carcinoma/patología , Quinasa de Punto de Control 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Adulto , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteína BRCA1/metabolismo , Carcinoma/metabolismo , Carcinoma Papilar , Quinasa de Punto de Control 2/metabolismo , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismo , Población Blanca
4.
J Clin Med ; 13(3)2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38337479

RESUMEN

A complete gonadal dysgenesis (CGD) with 46,XY karyotype is known as the Swyer syndrome and belongs to the group of 46,XY differences of sex development (DSD). The main problem in patients with Swyer syndrome is the delayed puberty and primary amenorrhea. Moreover, intrabdominal dysgenetic gonads in the patient with genetic material of a Y chromosome may conduce to the development of gonadal tumors, such as gonadoblastoma or germinoma. The management of such patients is based on preventive excision of dysgenetic gonads and long-term hormonal replacement therapy. Sporadic cases are considered more common than familial cases. This paper presents two siblings with Swyer syndrome in whom gonadoblastoma was found. A thorough review of familial CGD with 46,XY DSD in the literature from the last 15 years suggests that the risk of gonadal tumors could be increased in familial compared to sporadic cases (66.6% vs. 15-45%, respectively).

5.
Biology (Basel) ; 12(4)2023 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-37106694

RESUMEN

circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer.

6.
Proc Natl Acad Sci U S A ; 106(5): 1502-5, 2009 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-19164563

RESUMEN

Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.


Asunto(s)
MicroARNs/genética , Polimorfismo de Nucleótido Simple , Precursores del ARN/genética , Neoplasias de la Tiroides/genética , Apoptosis , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Heterocigoto , Humanos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/patología
7.
Am J Case Rep ; 23: e936135, 2022 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-36271606

RESUMEN

BACKGROUND Brown and jaw tumors are rare entities of poorly understood etiology that are regarded as end-stage of bone remodeling in patients with long-lasting and chronic hyperparathyroidism. Jaw tumors are mainly diagnosed in jaw tumors syndrome (HPT-JT syndrome) and are caused by mutation in the CDC73 gene, encoding parafibromin, a tumor suppressing protein. The aim of this work is to present 4 cases of patients in whom the genetic mutation of the CDC73 gene and clinical presentation coexist in an unusual setting that has not yet been described. CASE REPORT We present cases of 4 patients with primary hyperparathyroidism. Three were diagnosed with brown tumors (located in long bones, ribs, iliac, shoulders) and 1 with brown and jaw tumors. Expression of parafibromin in affected parathyroid tissues were analyzed. In patients without positive parafibromin staining, we searched for CDC73 mutation using next-generation sequencing. Parafibromin staining was positive in 1 patient with brown tumors and was negative in 2 individuals with brown tumors and 1 with brown and jaw tumors. CDC73 mutation was detected in two-thirds of patients (60%) with negative staining for parafibromin and brown tumors. MEN1 mutation was found in the patient with brown tumor and positive staining for parafibromin. CONCLUSIONS Patients with hyperparathyroidism and coexistence of brown tumors or jaw tumors might have decreased expression of parafibromin in parathyroid adenoma tissue, which might be caused by CDC73 mutation and suggest a genetic predisposition. Further research on much larger study groups is needed.


Asunto(s)
Fibroma , Hiperparatiroidismo Primario , Neoplasias Maxilomandibulares , Neoplasias de las Paratiroides , Humanos , Hiperparatiroidismo Primario/diagnóstico , Hiperparatiroidismo Primario/genética , Proteínas Supresoras de Tumor/genética , Neoplasias Maxilomandibulares/genética , Neoplasias Maxilomandibulares/complicaciones , Neoplasias Maxilomandibulares/patología , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/diagnóstico , Factores de Transcripción
8.
Proc Natl Acad Sci U S A ; 105(20): 7269-74, 2008 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-18474871

RESUMEN

Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.


Asunto(s)
Carcinoma/genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Tiroides/genética , Alelos , Carcinoma/etiología , Estudios de Casos y Controles , Línea Celular Tumoral , Estudios de Cohortes , Genotipo , Humanos , MicroARNs/biosíntesis , MicroARNs/metabolismo , Mutación , Proto-Oncogenes Mas , Neoplasias de la Tiroides/etiología , Transfección
9.
J Pers Med ; 11(4)2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33920896

RESUMEN

Atypical hemolytic uremic syndrome (aHUS) is a rare disease triggered by dysregulation of the alternative complement pathway, consisting of a characteristic triad of nonimmune hemolytic anemia, thrombocytopenia, and renal failure. The risk of aHUS onset, recurrence, and allograft loss depends on the genetic background of a patient. We show a series of cases from a single family whose five members were affected by aHUS and presented distinct clinical outcomes. Next-generation sequencing revealed combined mutations in both complement factor H and membrane cofactor protein CD46. Out of eight siblings, aHUS affected three adult brothers, and, subsequently, affected two children of an unaffected sister. The first patient died due to aHUS, and two other brothers underwent successful kidney transplantation with no aHUS recurrence. The younger, 10-month-old child presented with a severe course of the disease with cardiac involvement and persistent hemolytic anemia limited by eculizumab, while the 2-year-old recovered completely on eculizumab. The study shows a highly variable disease penetrance.

10.
Mol Genet Genomic Med ; 9(3): e1594, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33486847

RESUMEN

BACKGROUND: Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients' phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. METHODS: We employed next-generation sequencing to identify mutations in culpable genes. RESULTS AND CONCLUSION: In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients' family revealed that the mutation occurred de novo in the proband and was transmitted to his 26-month-old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Braquidactilia/genética , Adulto , Braquidactilia/patología , Preescolar , Humanos , Masculino , Mutación Missense , Linaje , Fenotipo
11.
Mol Neurobiol ; 56(6): 4346-4363, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30315479

RESUMEN

Bezafibrate (BZ) regulates mitochondrial biogenesis by activation of PPAR's receptors and enhancing the level of PGC-1α coactivator. In this report, we investigated the effect of BZ on the expression of genes (1) that are linked to different pathways involved in mitochondrial biogenesis, e.g., regulated by PPAR's receptors or PGC-1α coactivator, and (2) involved in neuronal or astroglial fate, during neural differentiation of hiPSC. The tested cell populations included hiPSC-derived neural stem cells (NSC), early neural progenitors (eNP), and neural progenitors (NP). RNA-seq analysis showed the expression of PPARA, PPARD receptors and excluded PPARG in all tested populations. The expression of PPARGC1A encoding PGC-1α was dependent on the stage of differentiation: NSC, eNP, and NP differed significantly as compared to hiPSC. In addition, BZ-evoked upregulation of PPARGC1A, GFAP, S100B, and DCX genes coexist with downregulation of MAP2 gene only at the eNP stage of differentiation. In the second task, we investigated the cell sensitivity and mitochondrial biogenesis upon BZ treatment. BZ influenced the cell viability, ROS level, mitochondrial membrane potential, and total cell number in concentration- and stage of differentiation-dependent manner. Induction of mitochondrial biogenesis evoked by BZ determined by the changes in the level of SDHA and COX-1 protein, and mtDNA copy number, as well as the expression of NRF1, PPARGC1A, and TFAM genes, was detected only at NP stage for all tested markers. Thus, developmental stage-specific sensitivity to BZ of neurally differentiating hiPSC can be linked to mitochondrial biogenesis, while fate commitment decisions to PGC-1α (encoded by PPARGC1A) pathway.


Asunto(s)
Bezafibrato/farmacología , Diferenciación Celular/efectos de los fármacos , Células Madre Pluripotentes Inducidas/citología , Neuronas/citología , Biogénesis de Organelos , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Ciclooxigenasa 1/metabolismo , ADN Mitocondrial/genética , Complejo II de Transporte de Electrones/metabolismo , Dosificación de Gen , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estándares de Referencia , Reproducibilidad de los Resultados
12.
J Clin Endocrinol Metab ; 93(3): 1077-81, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18073300

RESUMEN

CONTEXT: IL-23 and its receptor (IL-23R) guide T cells toward the T-helper 17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis. OBJECTIVE: Our objective was to determine whether variants in the IL-23R gene are associated with Graves' disease (GD) and Graves' ophthalmopathy (GO). DESIGN AND PARTICIPANTS: A total of 216 North American Caucasian GD patients and 368 healthy controls were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using the TaqMan allelic discrimination assays (Applied Biosystems, Foster City, CA), and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. RESULTS: The A allele of rs2201841 was present in 78.8% of GD patients with GO and 64.7% of controls [P=1.1x10(-4); odds ratio (OR)=2.04]; the AA genotype was also significantly increased in GO patients compared with controls (62.5 and 41%, respectively; P=1.0x10(-4); OR=2.4). The C allele of rs10889677 was present in 78.6% of GO patients and 64.5% of controls (P=1.3x10(-4); OR=2.03), and the CC genotype was also significantly increased in GO patients vs. controls (62.1 and 41.0%, respectively; P=1.4x10(-4); OR=2.36). The TT genotype of rs7530511 was significantly associated with GD, but not specifically with GO; it was present in 2.5% of GD patients and 0.3% of controls (P=0.02; OR=9.4). The rs11209026 SNP, which is the most strongly associated with Crohn's disease, was not associated with GD or GO in our data set. CONCLUSIONS: Variants in the IL-23R gene are strongly associated with GO. These variants may predispose to GO by changing the expression and/or function of IL-23R, thereby promoting a proinflammatory signaling cascade.


Asunto(s)
Autoinmunidad , Predisposición Genética a la Enfermedad , Oftalmopatía de Graves/genética , Interleucina-23/fisiología , Receptores de Interleucina/genética , Células TH1/inmunología , Glándula Tiroides/inmunología , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT4/fisiología , Células TH1/clasificación
13.
Methods Mol Biol ; 1823: 69-85, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29959675

RESUMEN

The analysis of microRNA expression patterns provides new insights into numerous cellular processes and their aberrances in diseases. Despite its potential pitfalls, the quantitative real-time polymerase chain reaction (qPCR) is the most commonly used tool for microRNA profiling. The method requires extraction and quality analysis of RNA, which is further reverse transcribed using specific primers and used as a template in a qPCR reaction. All these elements have been addressed in this chapter.


Asunto(s)
Perfilación de la Expresión Génica/métodos , MicroARNs , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , MicroARNs/biosíntesis , MicroARNs/genética
14.
Methods Mol Biol ; 1823: 87-101, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29959676

RESUMEN

Next-generation sequencing (NGS) enables the analysis of both microRNA expression and sequence, allowing for elucidation of a comprehensive landscape of miRNAs in a given tissue and sample type. NGS analysis requires high-quality RNA extraction and preparation of microRNA libraries. In this chapter, we describe the methods used for RNA extraction from tissue specimens, serum, cytological slides, and formalin-fixed paraffin-embedded samples. Although the described library preparation and sequencing approaches are based on Illumina NextSeq 500 sequencing technology, the presented principles shall be compatible with other commercially available sequencing platforms.


Asunto(s)
Biblioteca de Genes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , MicroARNs , Animales , Secuenciación de Nucleótidos de Alto Rendimiento/instrumentación , Humanos , MicroARNs/química , MicroARNs/genética , MicroARNs/aislamiento & purificación
15.
Endokrynol Pol ; 69(1): 34-74, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29442352

RESUMEN

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].


Asunto(s)
Sociedades Médicas , Neoplasias de la Tiroides/diagnóstico , Endocrinología , Femenino , Humanos , Masculino , Oncología Médica , Patología , Polonia , Neoplasias de la Tiroides/terapia
16.
Int J Mol Med ; 19(1): 181-6, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17143563

RESUMEN

Graves disease (GD) is an autoimmune disorder with genetic predisposition. The polymorphisms 47A-->G (Arg16Gly) and 79C-->G (Gln27Glu) of the adrenergic beta-2 receptor (ADRB2) gene in the 5q32 region affect the functional reaction to adrenergic stimulation, which contributes to the regulation of immunological response. The -367T-->C polymorphism within the 5'-leading regulatory sequence affects ADRB2 transcriptional activity. The aim of the present study was to investigate whether ADRB2 gene variants are associated with susceptibility to GD. All polymorphisms were studied in Polish GD patients (n=300) and healthy control subjects without a family history of autoimmune disorders (n=301). Genotypes were determined by the MassARRAY system (Sequenom, San Diego, CA). Gly16 and Gln27 allele frequencies were 61.4% and 55.2% among healthy controls, almost the same as previously reported in 4441 white participants of a cardiovascular health study. We found a higher risk of GD in Gln27 carriers (CC or CG genotypes) than in Glu27 homozygous (GG genotype) participants (OR=1.99, 95% CI: 1.27-3.12, p=0.003, pcorr=0.03). The frequency of the 79GG protective genotype was significantly smaller in the GD patients without symptoms of Graves ophthalmopathy compared to controls (10% vs 22%, OR=0.41, 95% CI: 0.234-0.706, p=0.0017, pcorr=0.015). We didn't find any association of -367T--> or 47A-->G genotypes/alleles with Graves disease, however, haplotype analysis has shown a significant difference in haplotype distribution between patients and controls (the global p=0.001) with increased -367T/47A/79C haplotype frequency in GD patients compared to controls (34% vs 25%, p=0.00073, pcorr=0.0044). In conclusion, Gln27 carriers (79CC or 79GC genotypes) have increased risk of Graves disease. Our results suggest that ADRB2 plays a role in susceptibility to Graves disease in humans.


Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Oftalmopatía de Graves/genética , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Estudios de Casos y Controles , Niño , Femenino , Frecuencia de los Genes , Enfermedad de Graves/epidemiología , Oftalmopatía de Graves/epidemiología , Humanos , Persona de Mediana Edad
17.
Oncotarget ; 8(30): 49191-49200, 2017 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-28423361

RESUMEN

BACKGROUND: Adrenocortical carcinoma is a rare finding among common adrenocortical tumors, but it is highly aggressive and requires early detection and treatment. Still, the differential diagnosis between benign and malignant lesions is difficult even for experienced pathologists and there is a significant need for novel diagnostic methods. In this study we aimed to reveal a complete set of microRNAs expressed in the adrenal gland and to identify easily detectable, stable and objective biomarkers of adrenocortical malignancy. METHODS: We employed next-generation sequencing to analyze microRNA profiles in a unique set of 51 samples, assigned to either a learning dataset including 7 adrenocortical carcinomas (ACCs), 8 adrenocortical adenomas (AAs) and 8 control samples (NAs), or a validation dataset including 8 ACCs, 10 AAs and 10 NAs. The results were validated in real-time Q-PCR. RESULTS: We detected 411 miRNAs expressed in 1763 length isoforms in the examined samples. Fifteen miRNAs differentiate between malignant (ACC) and non-malignant (AA + NA) tissue in the test set of independent samples. Expression levels of 6 microRNAs, miR-503-5p, miR-483-3p, miR-450a-5p, miR-210, miR-483-5p, miR-421, predict sample status (malignancy/non-malignancy) with at least 95% accuracy in both datasets. The best single-gene malignancy marker, miR-483-3p, has been validated by real-time RT PCR. CONCLUSIONS: As a result of the study we propose clinically valid and easily detectable biomarkers of adrenocortical malignancy that may significantly facilitate morphological examination. Since microRNAs can be detected in blood, the study brings tools for development of non-invasive diagnostics of adrenocortical carcinomas.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Biomarcadores de Tumor , Secuenciación de Nucleótidos de Alto Rendimiento , MicroARNs/genética , Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Biología Computacional/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Clasificación del Tumor , Curva ROC
18.
Sci Rep ; 7(1): 9942, 2017 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-28855631

RESUMEN

MicroRNAs, non-coding regulators of gene expression, are known culprits of thyroid cancer. Using next-generation sequencing, we identified a novel microRNA gene, encoded within an important thyroid regulator - thyroglobulin, and analyzed its functionality in the thyroid gland. In vitro and in silico analyses proved that the novel miR-TG is processed from the precursor, and co-expressed with thyroglobulin. Both genes are specific for thyroid tissue and downregulated in papillary thyroid carcinoma by 44% (p = 0.04) and 48% (p = 0.001), respectively. Putative target genes for miR-TG were identified using in silico tools, which pinpointed MAP4K4, an oncogene upregulated in thyroid cancer. Analysis of transcriptome by RNA-seq revealed that overexpression of miR-TG in PTC-derived cell line led to downregulation of several genes, including MAP4K4 (fold change 0,82; p = 0.036). The finding was confirmed by SQ-PCR (fold change 071; p = 0.004). Direct interaction between miR-TG and MAP4K4 was confirmed in the luciferase assay (p = 0.0006). Functional studies showed increase proliferation in K1 cell line transfected with miR-TG. We propose that in normal thyroid miR-TG plays a fine-tuning effect on the maintenance of MAPK pathway, inhibiting the expression of miR's target MAP4K4. This regulation is disturbed in cancer due to downregulation of the novel, thyroglobulin-embedded microRNA, characterized in this study.


Asunto(s)
Regulación hacia Abajo , Péptidos y Proteínas de Señalización Intracelular/genética , MicroARNs/genética , Proteínas Serina-Treonina Quinasas/genética , Tiroglobulina/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Regiones no Traducidas 3' , Línea Celular Tumoral , Simulación por Computador , Regulación Neoplásica de la Expresión Génica , Células HeLa , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , MicroARNs/metabolismo , Especificidad de Órganos , Análisis de Secuencia de ARN , Tiroglobulina/metabolismo , Glándula Tiroides/metabolismo
19.
Oncotarget ; 8(4): 6475-6482, 2017 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-28031538

RESUMEN

Papillary Thyroid Carcinoma (PTC) displays one of the highest familiality scores of all cancers as measured by case-control studies, yet only a handful of genes have been implicated until now. Variants in microRNAs have been associated with the risk of several cancers including PTC but the magnitude of this involvement is unclear. This study was designed to test to what extent genomic variants in microRNAs contribute to PTC risk. We used SOLiD technology to sequence 321 genomic regions encoding 427 miRNAs in one affected individual from each of 80 PTC families. After excluding variants with frequency ≥ 1% in 1000 Genomes Phase 1 (n = 1092) we detected 1978 variants. After further functional filtering steps 25 variants in pre-miRs remained. Co-segregation was observed for six out of 16 tested miRNA variants with PTC in the families, namely let-7e, miR-181b, miR-135a, miR-15b, miR-320, and miR-484. Expression of miR-135a and miR-181b was tested in normal thyroid and tumor tissue from patients that carry the variants and a decrease in expression was observed. In vitro assays were applied to measure the effect of the variants on microRNAs' maturation. Four out of six variants were tested. Only the let-7e and miR-181b variants showed an effect on processing leading to lower levels of mature miRNA. These two variants were not detected in 1170 sporadic PTC cases nor in 1404 controls. Taken together, our data show that high penetrance germline sequence variants of miRNAs potentially predispose to a fraction of all PTC but are not common.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Papilar/genética , Variación Genética , MicroARNs/genética , Neoplasias de la Tiroides/genética , Animales , Biomarcadores de Tumor/metabolismo , Células COS , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Chlorocebus aethiops , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Células HEK293 , Herencia , Humanos , MicroARNs/metabolismo , Linaje , Fenotipo , Factores de Riesgo , Análisis de Secuencia de ARN , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Transfección
20.
Eur J Endocrinol ; 174(3): R89-98, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26503845

RESUMEN

MicroRNAs, short non-coding regulators of the gene expression, are subjects of numerous investigations assessing their potential use in the diagnostics and management of human diseases. In this review, we focus on studies that analyze the utility of microRNAs as novel diagnostic and therapeutic tools in follicular cell-derived thyroid carcinomas. This very interesting and promising field brings new insight into future strategies for personalized medicine.


Asunto(s)
Adenocarcinoma Folicular/genética , MicroARNs/genética , Neoplasias de la Tiroides/genética , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/terapia , Humanos , Medicina de Precisión , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/terapia
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