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1.
Artículo en Chino | MEDLINE | ID: mdl-32086913

RESUMEN

Objective:The aim of this study is to explore the genotype and hearing phenotype of deaf infants with mutation of GJB2 gene. Method:Subjects were 121 infants with GJB2 gene mutations who were treated in the Children's Hearing Diagnosis Center of Beijing Tongren hospital. All subjects were accepted to undertake the universal newborns hearing screening(UNHS) and series of objective audiometry, including auditory brainstem response, distortion product otoacoustic emission, auditory steady-state response and other audiological tests. All subjects were screened for nine pathogenic variants in four genes or all exons of the GJB2 gene, and then were diagnosed as infants with GJB2 gene mutations. Initially, analyzing their genotypes and hearing phenotypes generally. Then, the subjects were divided into two groups according to the genotypes: T/T group(truncated/truncated mutations, 89 cases) and T/NT group(truncated/non-truncated mutations, 32 cases). Chi-square test was used to analyze the results of UNHS, hearing degree, audiogram patterns and symmetry/asymmetry of binaural hearing phenotype. Eventually, analyzing the results of UNHS. Result:The most common truncated mutation was c.235delC(64.88%, 157/242) and the most common non-truncated mutation was c.109G>A(11.16%, 27/242). The homozygous mutation of c.235delC/c.235delC was the dominant in T/T group(38.84%, 47/121), and the compound heterozygous mutation of c.235delC/c.109G>A was the dominant in T/NT group(18.18%, 22/121). 81.82%(99/121) of subjects failed in UNHS, including 74.38%(90/121) with bilateral reference, 7.44%(9/121) with a single pass. The refer rate of UNHS of group T/T and T/NT were 86.52%(77/89) and 68.75%, respectively. There was a statistically significant difference between the two groups(P<0.05). 85.95%(104/121) of subjects were diagnosed as hearing loss and 14.05%(17/121) of subjects were diagnosed as normal hearing. The degree of hearing loss: profound, severe, moderate and mild were 31.40%(38/121), 19.01%(23/121), 24.79%(30/121) and 10.74%(13/121), respectively. There was no subjects with normal hearing in T/T group and individuals with severe and profound hearing loss accounted for the highest proportion(65.17%, 58/89), while in T/NT group, normal hearing accounted for 53.13%(17/32) and mild and moderate hearing loss accounted for the highest proportion(37.5%, 12/32). There was statistically significant difference between the two groups(P<0.05). Of 104 patients(208 ears) with hearing loss, the audiogram patterns: flat, descending, ascending, residual, Valley and other types were 49.03%(102/208), 12.02%(25/208), 8.65%(18/208), 7.69%(16/204), 3.36%(7/204) and 19.23%(40/204), respectively. The two most common types in T/T group were flat(47.19%, 84/178) and other types(20.22%, 36/178), while in T/NT group were flat(60.00%, 18/30) and ascending(20.00%, 6/30). There was statistically significant difference between the two groups(P<0.05). There were 50 cases(48.07%) with symmetrical hearing phenotype and 54 cases(51.93%) with asymmetrical hearing phenotype. Asymmetry was predominant in T/T group(53.93%, 48/89), and symmetry was predominant in T/NT group(60.00%, 9/15). There was no statistically significant difference between the two groups(P>0.05). Conclusion:In this study, c.235delC/c.235delC homozygous mutation was dominant in T/T group and c.235delC/c.109G>A heterozygous mutation was dominant in T/NT Group. The hearing phenotypes in T/T group were mostly bilateral asymmetric severe hearing loss, and those in T/NT Group were bilateral symmetric mild to moderate hearing loss, special attention should be paid to the audiological characteristics of different genotypes.


Asunto(s)
Conexinas/genética , Sordera/genética , Análisis Mutacional de ADN , Genotipo , Humanos , Lactante , Recién Nacido , Mutación , Fenotipo
2.
Artículo en Chino | MEDLINE | ID: mdl-32086922

RESUMEN

Objective:To detect 20 common deafness gene mutations in non- syndromic deafness patients in China using PCR- RDB, and analyze and summarize the mutation data to explore the clinical value of this method. Method:The PCR- RDB and Sanger sequencing were used to detect 20 common mutations of four deafness genes(GJB2, GJB3, SLC26A4 and mtDNA) in 500 patients with non- syndromic hearing loss . The Sanger sequencing was used to compare the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the deafness mutation detected by PCR- RDB. Result:A total of 500 samples were detected. 147 wild- type samples, 81 homozygous mutant samples, 240 heterozygous mutant samples, 32 composite heterozygous mutant samples were detected using the PCR- RDB within the range of 20 gene mutations, which were identical to the Sanger sequencing results. GJB2 c.235delC and SLC26A4 c.919- 2 A>G are the most common hotspot mutations in this study, followed by mtDNA m. 1555 A>G. Compared with the Sanger sequencing method, the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the real- time fluorescence PCR melting curve method were 100%, and the Kappa value was one. Conclusion:PCR reverse dot-blot hybridization is a simple, rapid, sensitive and specific method for detecting 20 mutations of 4 common deafness genes in Chinese population, it is expected to be used in clinical detection of deafness genes in the future.


Asunto(s)
Análisis Mutacional de ADN , Sordera/genética , China , Conexinas/genética , ADN Mitocondrial/genética , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Transportadores de Sulfato/genética
3.
BMC Med Genet ; 21(1): 27, 2020 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-32039712

RESUMEN

BACKGROUND: Stickler syndrome is the most common genetic cause of rhegmatogenous retinal detachment (RRD) in children, and has a high risk of blindness. Type I (STL1) is the most common subtype, caused by COL2A1 mutations. This study aims to analyze the mutation spectrum of COL2A1 and further elucidate the genotype-phenotype relationships in the East Asian populations with STL1, which is poorly studied at present. METHODS: By searching MEDLINE, Web of Science, CNKI, Wanfang Data, HGMD and Clinvar, all publications associated with STL1 were collected. Then, they were carefully screened to obtain all reported STL1-related variants in COL2A1 and clinical features in East Asian patients with STL1. RESULTS: There were 274 COL2A1 variants identified in 999 patients with STL1 from 466 unrelated families, and more than half of them were truncation mutations. Of the 107 STL1 patients reported in the East Asian population, it was found that patients with truncation mutations had milder systemic phenotypes, whereas patients with splicing mutations had severer phenotypes. In addition, several recurrent variants (c.3106C > T, c.1833 + 1G > A, c.2710C > T and c.1693C > T) were found. CONCLUSIONS: Genotype-phenotype correlations should certainly be studied carefully, contributed to making personalized follow-up plans and predicting prognosis of this disorder. Genome editing holds great potential for treating inherited diseases caused by pathogenic mutations. In this study, several recurrent variants were found, providing potential candidate targets for genetic manipulation in the future.


Asunto(s)
Artritis/genética , Enfermedades del Tejido Conjuntivo/genética , Análisis Mutacional de ADN , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Desprendimiento de Retina/genética , Artritis/epidemiología , Artritis/patología , Enfermedades del Tejido Conjuntivo/epidemiología , Enfermedades del Tejido Conjuntivo/patología , Enfermedades Hereditarias del Ojo , Estudios de Asociación Genética , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Sensorineural/patología , Humanos , Fenotipo , Desprendimiento de Retina/epidemiología , Desprendimiento de Retina/patología
4.
Zhonghua Er Ke Za Zhi ; 58(2): 101-106, 2020 Feb 02.
Artículo en Chino | MEDLINE | ID: mdl-32102145

RESUMEN

Objective: To analyze the genetic characteristics of a five generations pedigree with homozygous familial hypercholesterolemia (HoFH). Methods: Prospective study. Twenty family members included a proband diagnosed as familial hyperlipidemia at the cardiology Department of Xi'an Children's Hospital in October 2018 were research object. Clinical data were collected. Genome DNAs were extracted. Whole exons sequencing was performed on the proband using target capture next generation sequencing. Candidate gene mutation sites identified by bioinformatics were verified by Sanger sequencing in the family members. The genotype-phenotype correlation of the pedigree was analyzed between heterozygous mutation carriers and non-carriers. Results: The proband was a 7-years and 10-month-old boy. He was born with a roundgreen bean size yellow skin protuberance in the skin of the coccyx. Since the age of 3-4 years old, xanthoma-like lesions with a diameter of 0.5-1.5 cm gradually appeared in the skin of bilateral elbow joints, knee joints and Achilles tendon. The height, weight and intellectual development of the child were the same as those of normal children at the same age. No similar xanthoma-like lesion was found in the other family members. The proband's total cholesterol (TC) reached 18.16-21.24 mmol/L, and his low density lipoproteincholesterol (LDL-C) was 14.08-15.51 mmol/L. Carotid ultrasonography showed diffuse sclerotic plaques in bilateral carotid and vertebral arteries, and color Doppler echocardiography revealed aortic valve thickening and calcification. Gene testing identified that the proband carried a homozygous mutation C. 418G>A (p. E140K) in LDLR gene inherited from his parents who had a consanguineous marriage and carried a heterozygous mutation of LDLR-E140K, respectively.The TC, LDL-C and apolipoproteinB (ApoB) of LDLR-E140K gene heterozygous carriers ((8.40±0.13), (6.79±0.01) and (1.95±0.05) mmol/L, respectively) were significantly higher than those of non-carriers ((4.59±0.28), (3.35±0.39) and (0.86±0.10) mmol/L, t=7.269, 4.595, 6.311, respectively, P<0.05). Conclusions: LDLR-E140K gene homozygous mutation is first reported to be associated with most severe phenotype HoFH. The genotype-phenotype analysis of the pedigree shows that the clinical phenotype of the proband with homozygous mutation is the most serious, and all the heterozygous mutation carriers present with hypercholesterolemia phenotype. The investigation confirms that LDLR-E140K is the pathogenic variation of familial hyperlipidemia.


Asunto(s)
LDL-Colesterol/sangre , ADN/genética , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo I/genética , Receptores de LDL/genética , Válvula Aórtica/diagnóstico por imagen , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Ecocardiografía Doppler , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Lactante , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Proteínas de la Membrana , Mutación , Linaje , Fenotipo , Estudios Prospectivos
5.
Nat Rev Cardiol ; 17(4): 200-201, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32042138
6.
BMC Infect Dis ; 20(1): 7, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900105

RESUMEN

BACKGROUND: Mycoplasma sp. are well recognized as etiological agents of respiratory and sexually transmitted disease. Mycoplasma penetrans, a species of Mycoplasma sp., has been frequently detected in HIV-positive patients and associated with the progression of HIV-associated disease. To date, there is only a single case report describing M. penetrans as the causative agent of a severe respiratory tract infection in a HIV-negative patient. CASE PRESENTATION: In this report, we describe the case of M. penetrans bacteremia in a HIV-negative, 38-year-old, female, immunocompromised, solid organ transplant patient (combined kidney and pancreas transplantation in 2016), who was admitted to our hospital with anemic uterine bleeding and fever of 38.3 °C. Several hours before her admission at our university hospital, a latex bladder catheter was inserted into her uterus and she complained about fatigue, dizziness and ongoing vaginal bleeding. Laboratory examination showed severe anemia, but microbiological examination was inconspicuous (culture negative vaginal and cervical smears, negative urine culture). Bacterial blood cultures showed a growth signal after 4 h, but microscopic examination with Gram staining and subcultures on different agar media did not identify bacterial pathogens. To identify the bacterial cause of malignancy in the patient, metagenomic sequencing of the blood culture was performed that identified M. penetrans. CONCLUSION: Metagenomic sequencing identified M. penetrans in an immunosuppressed patient with culture-negative bacteremia. Clinicians should be aware of the opportunistic potential of M. penetrans that may cause severe infections in certain vulnerable patient populations and the limitations of culture and Gram staining for confirming the presence of fastidious bacterial pathogens like Mycoplasma spp.


Asunto(s)
Bacteriemia/diagnóstico , Huésped Inmunocomprometido , Metagenómica , Infecciones por Mycoplasma/diagnóstico , Mycoplasma penetrans , Infecciones del Sistema Respiratorio/diagnóstico , Adulto , Bacteriemia/genética , Bacteriemia/microbiología , Análisis Mutacional de ADN/métodos , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Femenino , Seronegatividad para VIH , Humanos , Trasplante de Riñón , Metagenoma , Metagenómica/métodos , Infecciones por Mycoplasma/genética , Infecciones por Mycoplasma/microbiología , Mycoplasma penetrans/genética , Mycoplasma penetrans/aislamiento & purificación , Trasplante de Páncreas , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/microbiología , Análisis de Secuencia de ADN
7.
BMC Infect Dis ; 20(1): 5, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31900106

RESUMEN

BACKGROUND: Cysteine-cysteine chemokine receptor 5 is the main HIV co-receptor involved in the virus and cell-to-cell spread. A variant of the CCR5 gene known as CCR5-Δ32 which is a product of 32 base pair deletion in the gene plays critical role in the infection and progression to AIDS. The study was carried out to determine the CCR5 genotype of HIV-infected subjects attending University of Calabar Teaching Hospital, Calabar. METHODS: A total of 100 subjects attending HIV clinic, University of Calabar Teaching Hospital were purposively recruited for this study. DNA was extracted from each sample using the Quick gDNA miniprep DNA extraction kit, Zymo Research. Polymerase chain reaction (PCR) was used in the amplification of CCR5 gene in each DNA in a 9700 ABI Thermo cycler and then resolved on 4% agarose gel electrophoresis. RESULT: Out of the 100 samples assessed, 100 (100%) were homozygous for the CCR5 wild type gene (CCR5-wt), while none (0%) was homozygous for the CCR5-Δ32 (mutant type), and heterozygosity was not observed. CONCLUSION: This study observed absence of CCR5-Δ32 deletion gene among the studied subjects in Calabar, implying lack of genetic advantage in HIV infection and possible rapid progression towards AIDS if other precautions are not checked.


Asunto(s)
Infecciones por VIH/genética , Receptores CCR5/genética , Estudios Transversales , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Heterocigoto , Hospitales de Enseñanza , Humanos , Masculino , Nigeria/epidemiología , Filogenia , Reacción en Cadena de la Polimerasa , Eliminación de Secuencia
8.
Zhonghua Yi Xue Za Zhi ; 100(2): 136-140, 2020 Jan 14.
Artículo en Chino | MEDLINE | ID: mdl-31937054

RESUMEN

Objective: Tuberous sclerosis complex (TSC) is a multi-system disease with TSC1 and TSC2 genes as the pathogenic genes. The purpose of our study was to analyze the gene mutation in patients with TSC with epilepsy as the main clinical manifestation. The relationship between genotype and phenotype, scalp EEG in patients was analyzed. Methods: The peripheral blood was extracted from 43 patients and their families. TSC gene was detected by second-generation sequencing. Long-term video EEG monitoring and MRI examination were performed to determine the onset area, seizure type and location of nodules. Results: 39 patients had TSC gene mutation, 4 patients did not detect the gene mutation.11 had TSC1 mutations and 28 had TSC2 mutations. 22 mutations were de novo. Patients with TSC2 mutations had earlier seizure and more nodules than patients with TSC1 mutations, but no significant difference in intelligence and spasm were observed. 28 patients had focal origin of scalp EEG, of which 85.7% of TSC2 mutations patients had focal origin. Conclusions: Patients of TSC2 mutations always has an early onset age. Although MRI shows multiple nodules, the onset of EEG is mainly focal origin.


Asunto(s)
Esclerosis Tuberosa , Análisis Mutacional de ADN , Electroencefalografía , Genotipo , Humanos , Mutación , Fenotipo , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa
9.
Anticancer Res ; 40(1): 435-441, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892598

RESUMEN

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Recurrencia Local de Neoplasia/patología , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Femenino , Grecia , Humanos , Mesilato de Imatinib/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
10.
Gene ; 731: 144360, 2020 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-31935506

RESUMEN

Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facies, postnatal growth deficiency, cardiac defects and skeletal anomalies. Studies have determined that pathogenic variants of the lysine-specific methyltransferase 2D (KMT2D) and lysine-specific demethylase 6A (KDM6A) genes are the major causes of KS. The two genes encode different histone-modifying enzymes that are found in the same protein complex that is critical for cell differentiation during development. Here we report the results from next-generation sequencing of genomic DNA from 13 patients who had a clinical diagnosis of KS based on facial dysmorphism and other KS-specific cardinal phenotypes. Nine of the 13 patients were confirmed to be carrying heterozygous pathogenic KMT2D variants, seven of which were truncating and two were missense substitutions. Overall, we uncovered 11 novel variants - nine in KMT2D and two in KDM6A. Seven of the novel variants (all KMT2D) were likely causative of the KS phenotype. Our study expands the number of naturally occurring KMT2D and KDM6A variants. The discovery of novel pathogenic variants will add to the knowledge on disease-causing variants and the relevance of missense variants in KS.


Asunto(s)
Anomalías Múltiples/genética , Anomalías Congénitas/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/epidemiología , Asia Sudoriental/epidemiología , Niño , Preescolar , Estudios de Cohortes , Anomalías Congénitas/epidemiología , Análisis Mutacional de ADN/métodos , Femenino , Enfermedades Hematológicas/epidemiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación INDEL , Lactante , Recién Nacido , Masculino , Mutación Missense , Fenotipo , Análisis de Secuencia de ADN , Enfermedades Vestibulares/epidemiología
11.
Cancer Sci ; 111(2): 739-748, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31799787

RESUMEN

There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.


Asunto(s)
Carcinoma Ductal Pancreático/cirugía , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Secundarias/cirugía , Neoplasias Pancreáticas/cirugía , Proteína Smad4/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/metabolismo , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/patología , Pancreatectomía , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Análisis de Secuencia de ADN , Proteína Smad4/genética , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética
12.
Acta Cytol ; 64(1-2): 124-135, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31509835

RESUMEN

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.


Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/métodos , Quiste Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Antígeno Carcinoembrionario/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Análisis Mutacional de ADN/métodos , Humanos , Inmunohistoquímica/métodos , Mutación , Quiste Pancreático/genética , Quiste Pancreático/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética
13.
World Neurosurg ; 133: e421-e427, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31526886

RESUMEN

BACKGROUND: In the era of integrated genomic-histologic analysis of brain tumors, new biomarkers have been introduced as diagnostic, prognostic, and therapeutic indicators. The analysis of the mutation in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 has provided important diagnostic and prognostic information for patients affected by diffuse glioma (i.e., the presence of the mutation has been related to an increased survival rate). The reference standard of IDH mutation detection has been its assessment in surgical specimens, immunohistochemistry, and/or genetic sequencing. Knowing the IDH status information preoperatively would be of great importance, because it has been related to tumor progression and the response to treatment. The oncometabolite 2-hydroxyglutarate (2HG), accumulated in gliomas with IDH mutation status, can be detected in vivo using magnetic resonance spectroscopy (MRS). METHODS: The 2HG-MRS technique remains technically challenging. We have summarized the results of the first pilot study in Australia, which included 10 patients affected by glioma. The data recorded from May 2017 to November 2018 were analyzed. RESULTS: In our exploratory study, we reached a sensitivity and specificity of 100%, confirming the strong predictive role of 2HG, as detected using MRS, in the diagnosis of glioma. CONCLUSION: In the present study, we have focused on methodological tips and future perspectives of the technique in the neuroimaging and neuro-oncological scenario. We would advocate the integration of 2HG-MRS into standard clinical practice.


Asunto(s)
Neoplasias Encefálicas/enzimología , Análisis Mutacional de ADN/métodos , Glioma/enzimología , Isocitrato Deshidrogenasa/análisis , Espectroscopía de Resonancia Magnética/métodos , Proteínas de Neoplasias/análisis , Neuroimagen/métodos , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Femenino , Predicción , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Neuroimagen/tendencias , Proyectos Piloto , Sensibilidad y Especificidad , Adulto Joven
14.
Ann R Coll Surg Engl ; 102(2): e42-e44, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31538800

RESUMEN

Erdheim-Chester disease is a rare infiltrative histiocytic disorder with around 800 cases being reported worldwide. Patients most commonly present with skeletal pain, but the condition has been shown to affect multiple other organs. We describe a rare presentation in which the disease infiltrated the sinuses and affected an ex-RAF pilot's vision. After extensive investigation of the elusive diagnosis, repeating of a molecular test using polymerase chain reaction analysis allowed for identification of a mutation (BRAF V600) ultimately leading to the diagnosis of Erdheim-Chester disease.


Asunto(s)
Ceguera/etiología , Enfermedad de Erdheim-Chester/diagnóstico , Sinusitis/etiología , Ceguera/terapia , Análisis Mutacional de ADN , Diagnóstico Diferencial , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/terapia , Hueso Etmoides/diagnóstico por imagen , Hueso Etmoides/patología , Hueso Etmoides/cirugía , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Osteotomía , Pilotos , Proteínas Proto-Oncogénicas B-raf/genética , Sinusitis/terapia , Hueso Esfenoides/diagnóstico por imagen , Hueso Esfenoides/patología , Hueso Esfenoides/cirugía , Tomografía Computarizada por Rayos X
15.
Scand J Immunol ; 91(1): e12811, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31378960

RESUMEN

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/etiología , Mutación , Fenotipo , Polisacáridos/inmunología , Biomarcadores , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Estudios de Seguimiento , Genotipo , Humanos , Inmunofenotipificación , Recién Nacido , Masculino , Tamizaje Neonatal , /etiología , Evaluación de Síntomas
16.
Bull Cancer ; 107(1): 113-128, 2020 Jan.
Artículo en Francés | MEDLINE | ID: mdl-31353136

RESUMEN

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


Asunto(s)
Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación Missense , Mutación Puntual , Antineoplásicos/uso terapéutico , Dominio Catalítico , Toma de Decisiones Clínicas , ADN de Neoplasias/análisis , Resistencia a Antineoplásicos/genética , Sustitución de Medicamentos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Biología Molecular , Dominios Proteicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Rol
17.
Int J Cancer ; 146(5): 1435-1444, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31335987

RESUMEN

The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next-generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.008-0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065-0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04-0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Análisis Mutacional de ADN , Everolimus/farmacología , Everolimus/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Riñón/patología , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/metabolismo , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sirolimus/análogos & derivados , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética
18.
Gynecol Oncol ; 156(1): 203-210, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31757465

RESUMEN

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


Asunto(s)
Proteínas Serina-Treonina Quinasas/genética , Neoplasias del Cuello Uterino/genética , Grupo de Ascendencia Continental Asiática/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Femenino , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Valor Predictivo de las Pruebas , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología
19.
Acta Cytol ; 64(1-2): 147-154, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-30995656

RESUMEN

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


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Neoplasias/diagnóstico , ADN de Neoplasias/genética , Humanos , Neoplasias/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
20.
Acta Cytol ; 64(1-2): 182-192, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31060038

RESUMEN

Aside from its diagnostic importance, urinary tract endoscopy is an uncomfortable, expensive, and time-consuming procedure. Patients with a history of urothelial carcinoma remain at an increased risk for recurrence and the development of de novo disease; most have had exposure to carcinogenic risk factors for decades prior to their first diagnosis that have bathed the entire urothelial tract. Consequently, monitoring these patients over their lifetime has made urothelial carcinoma one of the most expensive cancers for the US healthcare system. This expense has provided a financial incentive for academic and commercial groups to develop a test with a sufficient negative predictive value to reduce the frequency of surveillance procedures. Slide-based tests require a separate slide prepared from a split urine sample or from an additional urinary tract specimen. This process can place an additional burden on the laboratory due to changes in the workflow, especially if the split specimens need to be stored until a cytologic diagnosis is rendered (i.e., when used as a reflex test). Importantly, slide-based tests allow for the result to be directly correlated with cytomorphologic findings; however, these tests require the cells of interest to be present. Thus, slide-based tests suffer from the same sensitivity issues as urinary tract cytology. In contrast, slide-free tests do not require an additional slide to be prepared, and laboratory testing may be centralized to a core facility or performed on-site. Some tests detect the expression of altered or abnormally expressed subcellular material (proteins, DNA, etc.) in urothelial neoplasms, which are found in tumor cells and/or in the urine specimen when the proteins are either excreted or leaked from degenerating tumor cells. Slide-free tests may also be developed into point-of-care tests, meaning that the result may be available to the urologist but not to the cytopathologist. Since these proteins are often disassociated from the tumor cells that produce them, such tests may have a positive result even if tumor cells are absent in the tested specimen. Here we review critical concepts as well as several ancillary tests that have been developed for urinary tract specimens.


Asunto(s)
Carcinoma de Células Transicionales/diagnóstico , Citodiagnóstico/métodos , Neoplasias de la Vejiga Urinaria/diagnóstico , Urotelio/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/orina , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/metabolismo , Análisis Mutacional de ADN/métodos , Humanos , Hibridación Fluorescente in Situ/métodos , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Sistema Urinario/metabolismo , Sistema Urinario/patología , Urotelio/metabolismo
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