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1.
Arq Neuropsiquiatr ; 79(7): 612-623, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34468500

RESUMEN

BACKGROUND: Increasing numbers of mutations causing monogenic forms of Parkinson's disease (PD) have been described, mostly among patients in Europe and North America. Since genetic architecture varies between different populations, studying the specific genetic profile of Brazilian patients is essential for improving genetic counseling and for selecting patients for clinical trials. OBJECTIVE: We conducted a systematic review to identify genetic studies on Brazilian patients and to set a background for future studies on monogenic forms of PD in Brazil. METHODS: We searched MEDLINE, EMBASE and Web of Science from inception to December 2019 using terms for "Parkinson's disease", "genetics" and "Brazil". Two independent reviewers extracted the data. For the genes LRRK2 and PRKN, the estimated prevalence was calculated for each study, and a meta-analysis was performed. RESULTS: A total of 32 studies were included, comprising 94 Brazilian patients with PD with a causative mutation, identified from among 2,872 screened patients (3.2%). PRKN mutations were causative of PD in 48 patients out of 576 (8.3%). LRRK2 mutations were identified in 40 out of 1,556 patients (2.5%), and p.G2019S was the most common mutation (2.2%). CONCLUSIONS: PRKN is the most common autosomal recessive cause of PD, and LRRK2 is the most common autosomal dominant form. We observed that there was a lack of robust epidemiological studies on PD genetics in Brazil and, especially, that the diversity of Brazil's population had not been considered.


Asunto(s)
Enfermedad de Parkinson , Brasil , Europa (Continente) , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación , Enfermedad de Parkinson/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 829-832, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487523

RESUMEN

OBJECTIVE: To detect variants of NF1 gene among thirteen patients with neurofibromatosis type 1. METHODS: Genomic DNA was extracted from peripheral blood samples of the patients. High-throughput sequencing was employed to detect potential variants of the NF1 and NF2 genes. RESULTS: Thirteen pathogenic variants were identified among the patients, which included one NF1 deletion, three missense variants, three nonsense variants and six frameshifting variants. Among these, 10 variants have been associated with neurofibromatosis type 1. c.4180A>T (p.Asn1394Tyr), c.4217dupT (p.Leu1406fs) and c.1753dupT(p.Leu585Phefs*3) were unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, c.4180A>T (p.Asn1394Tyr) was predicted to be likely pathogenic (PS2+PM1+PM2+PP2), while c.4217dupT (p.Leu1406fs) and c.1753dupT (p.Leu585Phefs*3) were predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: Variants of the NF1 gene probably underlay the disease among these children. Above findings have enriched the the spectrum of NF1 gene variants.


Asunto(s)
Genes de Neurofibromatosis 1 , Neurofibromatosis 1 , Niño , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neurofibromatosis 1/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 833-837, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487524

RESUMEN

OBJECTIVE: To analyze gene variants in a Chinese pedigree with oculocutaneous albinism (OCA). METHODS: Gene sequencing of the proband and his parents was performed using chip capture high-throughput sequencing and Sanger sequencing techniques, and PolyPhen-2, SIFT, MutationTaster, and FATHMM software were used to predict the function of new variants. At the same time,the pedigree and variant genes of 4 albinism patients from this pedigree were analyzed. RESULTS: Sequencing results showed that the proband's TYR gene (NM_000372) has c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) compound heterozygous variants. The proband's father carries c.230G>A heterozygous variant, and the mother carries c.120_121insG heterozygous variant, indicating that the proband's two variants are from his father and mother. The former is a known missense variant, which can cause abnormal or loss of the original function of the protein polypeptide chain. The latter c.120_121insG(p.Asp42GlyfsTer35) is an unreported frameshift variant of the TYR gene subregion (EX1; CDS1). PolyPhen-2, SIFT, MutationTaster and FATHMM predictions are all prompted as "harmful variants". This variant caused the amino acid encoded protein to terminate prematurely, producing a truncated protein, which eventually formed a 76-amino acid short-type TYR protein instead of the 529-amino acid wild-type TYR protein. Through the pedigree analysis, the four patients in the pedigree are all of the same type of compound heterozygous variants, and the disease-causing genes are all from the patient's parents. They belong to a special form of consanguineous marriage within 5 generations. CONCLUSION: The compound heterozygous variants of c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) of the TYR gene may underlie the disease in this pedigree. The gene sequencing results enrich the variant spectrum of the TYR gene, and has facilitated molecular diagnosis for the patient.


Asunto(s)
Albinismo Oculocutáneo , Albinismo Oculocutáneo/genética , Consanguinidad , Heterocigoto , Humanos , Mutación , Linaje
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 838-840, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487525

RESUMEN

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with resistance to thyroid hormone syndrome (RTH). METHODS: Exons 7 to 10 of the THRbeta gene were sequenced for the proband and members of his pedigree. RESULTS: Three patients from the pedigree were identified. All have presented with palpitation, fatigue, goiter, elevated free thyroid hormone and free triiodothyronine, and normal or elevated thyrotropin. Genetic testing revealed that the proband, his mother, second sister and one of her daughters had carried a heterozygous c.1336T>A variant of the THRbeta gene, which resulted in substitution of Cysteine by Serine at position 446. The variant was unreported previously. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.1336T>A(p.Cys446Ser) variant of THRbeta gene was predicted to be lilely pathogenic(PM1+PM2+PM5+PP3). CONCLUSION: The c.1336T>A variant, identified in the exon 10 of the THRbeta gene, probably underlay the RTH in this pedigree. Genetic testing has validated the clinical diagnosis for this pedigree.


Asunto(s)
Genómica , Madres , Femenino , Heterocigoto , Humanos , Mutación , Linaje
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 841-844, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487526

RESUMEN

OBJECTIVE: To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis. METHODS: Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing. RESULTS: Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife. CONCLUSION: The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.


Asunto(s)
Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Anomalías Múltiples/genética , Cerebelo/anomalías , Cerebelo/diagnóstico por imagen , Anomalías del Ojo/genética , Femenino , Feto , Humanos , Mutación , Fenotipo , Embarazo , Retina/anomalías
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 873-876, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487534

RESUMEN

OBJECTIVE: To report the clinical manifestation and genetic characteristics of a child with Thiamine metabolism dysfunction syndrome 5. METHODS: Clinical data and genetic results were collected and analyzed. Peripheral blood samples of the child and their parents were collected for whole exome sequencing, and the functional effect of the variants on the TPK1 enzyme activity was verified by an in vitro assay. RESULTS: A four-year-old boy presented with preschool onset of ataxia were characterized. High-throughput sequencing identified a novel homozygous variant of TPK1 gene c.382G>A (p.Leu128Phe). His father and mother were both found carrying the variant. The variant protein showed a 30.9% reduction in TPK1 enzyme activity compared with the wildtype. CONCLUSION: A novel pathogenic variant has been identified in a boy with thiamine metabolic dysfunction syndrome type 5.


Asunto(s)
Pruebas Genéticas , Tiamina , Niño , Preescolar , Homocigoto , Humanos , Masculino , Mutación , Secuenciación del Exoma Completo
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 877-879, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487535

RESUMEN

OBJECTIVE: To explore the genetic basis for a patient diagnosed with tuberous sclerosis complex (TSC). METHODS: Peripheral blood samples of the patient and his parents were collected for the extraction of genomic DNA. Next generation sequencing (NGS) was carried out to detect potential variant, and the result was verified by Sanger sequencing. RESULTS: The patient was found to harbor a heterozygous c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene. The same variant was not found in his unaffected parents and 100 unrelated healthy controls. Based on the American College of Medical Genetics and Genomics guidelines, the variant was predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: The novel c.1053delG (p.Glu352SerfsX10) frameshifting variant of the TSC2 gene probably underlay the TSC in this patient.


Asunto(s)
Esclerosis Tuberosa , Genómica , Heterocigoto , Humanos , Mutación , Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 880-883, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487536

RESUMEN

OBJECTIVE: To explore the genetic etiology of a fetus with autosomal recessive polycystic kidney disease (ARPKD). METHODS: Prenatal ultrasonography has revealed oligohydramnios and abnormal structure of fetal kidneys. After careful counseling, the couple opted induced abortion. With informed consent, genomic DNA was extracted from the muscle sample of the abortus and peripheral blood samples of the couple. High throughput whole exome sequencing was carried out to detect potential variants in relation with the disease. Suspected variants were verified by Sanger sequencing. RESULTS: Prenatal ultrasound revealed increased size of fetal kidneys, with multiple hyperechos from the right kidney, and multiple hyperechos with anechoic masses within the left kidney. DNA sequencing revealed that the fetus has carried heterozygous variants of the PKHD1 gene, including c.7994T>C inherited from its father, and two heterozygous variants of the PKHD1 gene c.5681G>A from its mother. CONCLUSION: The compound heterozygous c.7994T>C and c.5681G>A variants of the PKHD1 gene probably underlay the pathogenesis of ARPKD in this fetus. Above results can provide guidance for subsequent pregnancies of the couple.


Asunto(s)
Riñón Poliquístico Autosómico Recesivo , Femenino , Feto , Pruebas Genéticas , Humanos , Mutación , Riñón Poliquístico Autosómico Recesivo/diagnóstico por imagen , Riñón Poliquístico Autosómico Recesivo/genética , Embarazo , Receptores de Superficie Celular/genética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 887-890, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487538

RESUMEN

OBJECTIVE: To explore the clinical features and disease-causing variants of a pediatric patient with fatal encephalopathy caused by mitochondrial peroxidase division deficiency, to identify the possible genetic causes of the disease and provide a basis for clinical diagnosis. METHODS: A child with fatal encephalopathy caused by mitochondrial peroxidase division deficiency in West China Second Hospital of Sichuan University was selected. The clinical manifestations, laboratory findings and disease-causing variant were analyzed. RESULTS: The main clinical symptoms of the patient were fever, headache and vomiting, followed by drug refractory epilepsy and progressive disturbance of consciousness. MRI showed deepening of sulcus, dilatation of bilateral ventricles, and multiple patch-like abnormal signals in paraventricular white matter, semioval center and subcortical white matter of bilateral frontal lobe. Gene detection showed a heterozygous missense variant c.1207C>T(p.Arg403Cys) in DNM1L, according to the American College of Medical Genetics and Genomics classification standards and guidelines for genetic variants, this variant was predicted to be pathogenic(PS1+PS2+PM2+PP3). After treated with gamma globulin, glucocorticoid, "mitochondrial cocktail therapy" and anti-epilepsy drugs, the condition of the patient was getting better, seizure attacks reduced and consciousness level improved. CONCLUSION: The c.1207C>T variant in DNM1L gene may be the disease-causing variant for the patient, and the result of genetic testing provides a basis for the clinical diagnosis in this case.


Asunto(s)
Epilepsia Refractaria , Peroxidasa , Niño , Dinaminas , Genómica , Humanos , Mitocondrias , Mutación , Convulsiones
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 891-894, 2021 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-34487539

RESUMEN

OBJECTIVE: To explore the genetic basis for a juvenile with maturity-onset diabetes of the young type 12(MODY12). METHODS: High-throughput sequencing was carried out to screen for the variants. Candidate variant was verified by Sanger sequencing. Pathogenity of the variant was predicted by searching the genetic databases and analysis by using bioinformatic software. RESULTS: Genetic testing indicated that the patient and his mother have both carried a heterozygous c.3976G>A variant (p.Glu1326Lys) in exon 32 of the ABCC8 gene. Prediction of the protein structure suggested the variant to be deleterious. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be uncertain significance. CONCLUSION: Whether the c.3976G>A variant of the ABCC8 gene is the cause of the disease in this patient or not depends on the functional studies and more case data. Above finding has enriched the spectrum of ABCC8 gene variants.


Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/genética , Pruebas Genéticas , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación
11.
Enzyme Microb Technol ; 150: 109870, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34489029

RESUMEN

The propeptide is a short sequence that facilitates protein folding. In this study, four highly active Rhizomucor miehei lipase (RML) mutants were obtained through saturation mutagenesis at three propeptide positions: Ser8, Pro35, and Pro47. The enzyme activities of mutants P35 N, P47 G, P47 N, and S8E/P35S/P47A observed at 40 °C, and pH 8.0 were 10.19, 7.53, 6.15, and 8.24 times of that wild-type RML, respectively. The S8E/P35S/P47A mutant showed good thermostability. After incubation at 40 °C for 1 h, 98.98 % of its initial activity remained, whereas wild-type RML retained only 78.76 %. This result indicated that the enhancement of hydrophilicity of 35- and 47- amino-acid residues could promote the interaction between the propeptide and the mature peptide and the enzyme activity and expression level. Highly conserved sites had a more significant impact on enzyme performance than did other sites, similar to the Pro35 and Pro47 mutants showed in this study. This study provides a new idea for protein modification: enzyme performance can be improved through propeptide regulation.


Asunto(s)
Lipasa , Rhizomucor , Lipasa/genética , Lipasa/metabolismo , Mutación , Pliegue de Proteína , Rhizomucor/genética
12.
Artículo en Ruso | MEDLINE | ID: mdl-34481439

RESUMEN

Neuronal ceroid lipofuscinosis type 6 (NCL 6) is a rare progressive neurodegenerative disease that belongs to the group of lysosomal storage diseases. A clinical and genetic description of NCL 6 in a Yakut family was carried out. The proband and her sibling showed characteristic clinical signs, including myoclonic epilepsy, ataxia, psychomotor regression, dementia, and visual impairment. The onset of the disease in the age range from 3-4 years. The disease is caused by the frameshift mutation c.396dupT (p.Val133CysfsTer18) in exon 4 of the CLN6 in a homozygous state, which was detected using targeted next generation sequencing. Diagnosis of NCL is difficult due to the pronounced genetic heterogeneity of the disease, as well as the similarity with other hereditary metabolic diseases in clinical manifestations. The method of DNA diagnostics of NCL type 6 using NGS and direct sequencing according to Sanger has been introduced into the practice of medical genetic counseling.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales , Preescolar , Femenino , Homocigoto , Humanos , Proteínas de la Membrana/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética
13.
BMC Gastroenterol ; 21(1): 339, 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34470610

RESUMEN

AIM: To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. METHODS: One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. RESULTS: In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype-genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. CONCLUSION: In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.


Asunto(s)
Proteínas de Transporte de Catión , ATPasas Transportadoras de Cobre , Degeneración Hepatolenticular , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Proteínas de Transporte de Catión/genética , China , ATPasas Transportadoras de Cobre/genética , Análisis Mutacional de ADN , Estudios de Asociación Genética , Genotipo , Degeneración Hepatolenticular/genética , Humanos , Mutación
14.
Am J Case Rep ; 22: e932252, 2021 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-34491978

RESUMEN

BACKGROUND Osimertinib is an oral third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced non-small cell lung cancer (NSCLC) with positive EGFR mutation. Rashes, nail toxicity, and diarrhea are common adverse events. Hematological adverse effects, including anemia, thrombocytopenia, and lymphocytopenia, have been reported. However, erythrocytosis has not been reported as an adverse event. To the best of our knowledge, we report the first case of acute lower extremity thrombosis presumably caused by osimertinib-induced erythrocytosis. CASE REPORT A 70-year-old man with epidermal EGFR-mutant advanced NSCLC presented with acute left sural pain. The patient's left foot was cold, and peripheral arterial Doppler signals were absent. He had developed erythrocytosis of unknown etiology during osimertinib therapy. Hemoglobin (Hb) and hematocrit were 22.6 g/dL and 62.5%, respectively. Contrast-enhanced computed tomography showed thrombotic occlusion of the popliteal artery. Other than erythrocytosis, there was no possible cause of arterial thrombosis. Osimertinib was discontinued immediately because the NSCLC started to resist treatment and was presumed to be the cause of erythrocytosis. He received endovascular treatment (EVT). Following serial EVT and debridement, his fourth toe was amputated for necrosis. Erythrocytosis persisted 8 months during osimertinib therapy. Hb levels decreased to 15.4 mg/dL due to blood loss complicated with catheter thrombectomy and remained normal for 20 months after osimertinib discontinuation. The patient died of cancer progression. CONCLUSIONS This case suggests the erythrocytosis was possibly caused by osimertinib. We may need to monitor Hb levels during osimertinib therapy and be alert to thrombosis once Hb starts to rise.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Policitemia , Trombosis , Acrilamidas , Anciano , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Extremidad Inferior , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Mutación , Policitemia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos
15.
Ceska Gynekol ; 86(4): 258-262, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34493051

RESUMEN

OBJECTIVE: The main objective of the article is to clearly inform healthcare professionals about the newly implemented molecular classification of endometrial cancer into practice. METHODS: Summary of current knowledge, recommendations and new procedures relating to molecular genetic examination of the tissues of patients with endometrial carcinoma. RESULTS: Endometrial cancer is currently dia-gnosed on the base of histopathological morphology. According to the classical Bokhman division, we distinguish between two relatively wide groups of tumors which are different in pathogenesis: type I - estrogen-dependent tumors, clinically usually indolent, and type II - non-endometroid tumors, clinically aggressive, without dependence on estrogen stimulation. This classification fulfills a didactic purpose and provides easy orientation for epidemiological data, but is not suitable for stratification due to the overlap of clinical, pathological and molecular features. The Cancer Genome Atlas project classifies endometrial tumors into 4 groups based on molecular genetic features. CONCLUSION: Integration of the histopathological findings along with molecular classification appears to be the best approach for evaluating each individual tumor. This will help to achieve the ideal stratification of patients for treatment  regimens.


Asunto(s)
Carcinoma Endometrioide , Neoplasias Endometriales , Neoplasias Endometriales/genética , Femenino , Humanos , Mutación
16.
Anticancer Res ; 41(9): 4417-4422, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34475063

RESUMEN

BACKGROUND/AIM: Ovarian carcinoma is the fifth leading cause of cancer-related deaths in women in the United States. Serous papillary carcinoma is the most common histological type of ovarian carcinoma that often goes undetected until it has spread within the pelvis and abdomen leading to poor prognosis. Translation of next-generation sequencing (NGS) technology into personalized medicine and identification of new potential targets for therapeutic applications may be helpful. CASE REPORT: We report a case of a 59-year-old female who initially presented in the emergency department with increasing abdominal girth, and bloating. Computed tomography showed ascites and omental and pelvic masses. Fine needle biopsy of the omental mass showed high-grade papillary adenocarcinoma consistent with high-grade ovarian serous carcinoma. She was treated with chemotherapy followed by debulking surgery. Primary ovarian serous carcinoma and synchronous primary fallopian tube serous carcinoma with multiple leiomyomas were identified in the surgical specimen. Pleural biopsy was also positive for carcinoma. NGS and programmed death-ligand 1 (PD-L1) expression testing were performed in the ovarian serous carcinoma. The results showed mutations of breast cancer type 1 (BRCA1) and type 2 (BRCA2), tumor protein p53 (TP53) (c.524G>A at pR175H), and heat shock protein 90 alpha family class B member 1 (HSP90AB1) (p.R456C), as well as low RNA expression score of PD-L1. CONCLUSION: Identification of these mutations and PD-L1 abnormality at the diagnosis of ovarian carcinoma may shed light for clinicians to provide targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors for ovarian serous carcinoma. This is the first documented case of ovarian serous carcinoma to have found a HSP90AB1 (p.R456C) mutation.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Neoplasias de las Trompas Uterinas/genética , Proteínas HSP90 de Choque Térmico/genética , Leiomiomatosis/genética , Neoplasias Primarias Múltiples/genética , Neoplasias Ováricas/genética , Biopsia con Aguja Fina , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/cirugía , Procedimientos Quirúrgicos de Citorreducción , Quimioterapia , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/cirugía , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leiomiomatosis/tratamiento farmacológico , Leiomiomatosis/patología , Leiomiomatosis/cirugía , Persona de Mediana Edad , Mutación , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Análisis de Secuencia de ADN , Tomografía Computarizada por Rayos X , Estados Unidos
17.
Anticancer Res ; 41(9): 4609-4617, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34475089

RESUMEN

BACKGROUND/AIM: This study aimed to assess the yield of an Oncomine comprehensive assay v3 (OCAv3)-based next-generation sequencing (NGS) analysis for detecting anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusions in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: NGS data from 85 NSCLC cases were reviewed. ALK and ROS1 fusion status was compared to conventional tests. RESULTS: ALK or ROS1 fusion reads were detected in 17 NSCLC cases. Results in 10 NSCLC cases showed concordance with conventional tests, high-count fusion reads, a lack of mutually exclusive mutations of ALK or ROS1, and frequent signet-ring cell component. Seven NSCLC cases showing discordant results exhibited low to intermediate fusion read counts and mutations mutually exclusive from ALK or ROS1. CONCLUSION: Cases showing high-count fusion reads in OCAv3-based NGS have a strong possibility of carrying ALK or ROS1 fusion. Cases with low- to intermediate-count fusion reads should be interpreted with caution and may require additional confirmative tests.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Análisis de Secuencia de ARN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Análisis Citogenético , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
19.
Rinsho Ketsueki ; 62(8): 1060-1069, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34497192

RESUMEN

Myeloproliferative neoplasms (MPN) are caused by somatic mutations in hematopoietic stem/progenitor cells and result in excessive increase in the blood cell mass in the peripheral blood and/or fibrosis in the bone marrow. JAK2, CALR, and MPL mutations are well-known driver mutations of MPN and are widely applied as diagnostic markers of MPN. Moreover, several studies using massive parallel sequencing technologies have shown that mutations in ASXL1, EZH2, SRSF2, and IDH1/2 affect the prognosis of overt primary myelofibrosis and have further clarified that the mutation order may influence the MPN phenotype. More recently, our group identified that CREB3L1 mRNA was overexpressed in a platelet- and megakaryocyte-specific manner in driver mutation positive MPN and that the quantitation of this gene expression can be used as a diagnostic marker for MPN. In this educational lecture, we discuss the clinical impacts of the mutations frequently identified in MPN patients.


Asunto(s)
Trastornos Mieloproliferativos , Neoplasias , Calreticulina/genética , Humanos , Janus Quinasa 2/genética , Japón , Mutación , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética
20.
Rinsho Ketsueki ; 62(8): 1121-1130, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34497199

RESUMEN

Lymphoma comprises a group of diseases characterized by neoplastic proliferation of mature B, T, and NK cells. This disease entity is widely recognized to be clinically, pathologically, molecularly, and genetically heterogeneous. The classification of lymphomas was classically based on morphology and immunology, but recent dramatic advances in next-generation sequencing technology have revealed various genetic alterations in lymphomas, which influenced the revision of the WHO classification in 2017. Accumulating evidence on genetic alterations has enabled the development of more accurate diagnostic strategies and prognostic markers. Moreover, these findings provide opportunities to exploit new therapeutics that target genetic alterations, which would facilitate the use of precision medicine in lymphomas. Here, we briefly review the fundamental methods of genetic analysis using next-generation sequencing technology and describe the entire scenario of genetic alterations, focusing on the recent major studies that have revealed various genetic alterations in each lymphoma subtype and present a detailed discussion of the results and methods.


Asunto(s)
Linfoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células Asesinas Naturales , Linfoma/diagnóstico , Linfoma/genética , Mutación , Medicina de Precisión
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