RESUMEN
Pemphigus is a group of rare, lifethreatening bullous autoimmune diseases that affect the skin and mucous membranes and are associated with high morbidity and morbidity. HLA class II genes, particularly HLA-DRB1 and HLA-DQB1, play roles in pemphigus. The aim of this paper is to investigate the susceptibility of HLA class II DRB1 and DQB1 alleles in Vietnamese patients with pemphigus vulgaris (PV) or pemphigus foliaceus (PF). The study enrolled 31 participants (22 with PV, 9 with PF) with diagnoses confirmed by clinical manifestations, histopathology, and direct immunofluorescence from November 2019 to June 2020. The HLA polymorphisms were determined by Sanger sequencing. The HLA-DRB1 and HLA-DQB1 profiles of the 101 healthy individuals in the control group have been published previously. The frequencies of HLA-DRB1*14, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were significantly higher, whereas those of DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 were significantly lower, in the PV group than in the controls. The frequencies of DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 were significantly higher in the PF group than in the controls. Alleles HLA-DRB1*14:54, DRB1*14:04, DRB1*14:03, DRB1*14:01, DRB1*14:12, DRB1*13:07, DRB1*04:04, DRB1*03:02, DQB1*02:02, and DQB1*05:03 were associated with an increased risk of PV, whereas alleles DRB1*09:01, DRB1*12:02, DQB1*03:03, DQB1*05:01, and DQB1*06:01 might protect against PV. In PF, DRB1*14:54, DRB1*13:07, and HLA-DQB1*03:02 are promising susceptibility alleles.
RESUMEN
Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR, particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Variaciones en el Número de Copia de ADN , Metilación de ADN , Resistencia a Antineoplásicos/genética , Biopsia Líquida/métodos , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Cohortes , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana EdadRESUMEN
The identification and quantification of actionable mutations are critical for guiding targeted therapy and monitoring drug response in colorectal cancer. Liquid biopsy (LB) based on plasma cell-free DNA analysis has emerged as a noninvasive approach with many clinical advantages over conventional tissue sampling. Here, we developed a LB protocol using ultra-deep massive parallel sequencing and validated its clinical performance for detection and quantification of actionable mutations in three major driver genes (KRAS, NRAS and BRAF). The assay showed a 92% concordance for mutation detection between plasma and paired tissues and great reliability in quantification of variant allele frequency.
Asunto(s)
ADN Tumoral Circulante/genética , Neoplasias Colorrectales/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biopsia Líquida/métodos , Neoplasias Colorrectales/sangre , GTP Fosfohidrolasas/genética , Humanos , Proteínas de la Membrana/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth (CMT) disease and over 80 different mutations have been identified so far. This study analyzed the clinical and genetic characteristics of a Vietnamese CMT family that was affected by a novel GDAP1 mutation. METHODS: We present three children of a family with progressive weakness, mild sensory loss, and absent tendon reflexes. Electrodiagnostic analyses displayed an axonal type of neuropathy in affected patients. Sequencing of GDAP1 gene was requested for all members of the family. RESULTS: All affected individuals manifested identical clinical symptoms of motor and sensory impairments within the first three years of life, and nerve conduction study indicated the axonal degeneration. A homozygous GDAP1 variant (c.667_671dup) was found in the three affected children as recessive inheritance pattern. The mutation leads to a premature termination codon that shortens GDAP1 protein (p.Gln224Hisfs∗37). Further testing showed heterozygous c.667_671dup variant in the parents. DISCUSSION: Our study expands the mutational spectrum of GDAP1-related CMT disease with the new and unreported GDAP1 variant. Alterations in GDAP1 gene should be evaluated as CMT causing variants in the Vietnamese population, predominantly axonal form of neuropathy in CMT disease.