Structural maintenance of chromosome 4 gene expression in glioma and its clinical significance / 中华神经医学杂志

Objective:To analyze the expression of structural maintenance of chromosome 4( SMC4) gene in glioma and its clinical significance. Methods:(1) The SMC4 mRNA expression data of 749 glioma tissues and clinical data of these glioma patients were downloaded from Chinese Glioma genome Atlas (CGGA) database. Univariate Cox analysis and multivariate Cox analysis were used to analyze the independent influencing factors for poor prognosis in patients with glioma. Patients were divided into high SMC4 mRNA expression group and low SMC4 mRNA expression group; Kaplan-Meier method was used to draw the survival curve of these patients. Receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of SMC4 mRNA in 1-, 3- and 5-year survival of these patients. (2) The relationships between SMC4 mRNA expression levels in glioma tissues from cancer Genome Atlas (TCGA) database and overall survival of these glioma patients were analyzed by gene expression profiling interactive analysis (GEPIA). The SMC4 protein expressions in high-grade glioma (glioblastoma) and low-grade glioma were determined by human protein atlas (HPA) online database. (3) Genomic enrichment analysis was used to analyze and compare the differences of gene body (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway in gliomas between SMC4 mRNA high expression group and SMC4 mRNA low expression group. Co-expression analysis was performed to analyze the genes related to SMC4 mRNA. Results:(1) Multivariate Cox analysis showed that SMC4 mRNA ( HR=1.314, 95%CI: 1.209-1.428, P=0.000), glioma primary-recurrent-secondary (PRS) type, glioma WHO grading, age, chemotherapy, isocitrate dehydrogenase ( IDH) mutation and 1P/19q deletion were independent influencing factors for poor prognosis of glioma patients. Survival analysis showed that the overall survival of patients with low SMC4 mRNA expression was significantly higher than that of patients with high SMC4 mRNA expression ( P<0.05). The area under the curve (AUC) of ROC was 0.712, 0.784 and 0.791, respectively, in predicting 1-year survival rate, 3-year survival rate and 5-year survival rate. (2) SMC4 mRNA expressions in low-grade and high-grade gliomas were statistically lower than those in normal control brain tissue ( P<0.05). The overall survival of low-grade glioma patients with low SMC4 mRNA expression was significantly higher than that of patients with SMC4 mRNA high expression ( P<0.05). There was no significant difference in overall survival between high-grade glioma patients with low SMC4 mRNA expression and high SMC4 mRNA expression ( P>0.05). The SMC4 protein expression in low-grade glioma was significantly higher than that in high-grade glioma. (3) Genome enrichment analysis showed that GO enriched in gliomas with high SMC4 mRNA expression was about nuclear chromosome aggregation, protein complex driving, cell cycle meiotic and process of meiotic cell cycle. KEGG enrichment included cell cycle, DNA replication, mismatch repair, P53 signaling pathway, pancreatic cancer and other related pathways. Gene co-expression analysis showed that the first 5 genes, including BUB1, WEE1, CENPL, KIF23 and SGOL2, were positively correlated with SMC4 mRNA expression; and the first 5 genes, including FBXW4, PNMAL2, MATK, PASL10A and CTD-2210P24.4, were negatively correlated with SMC4 mRNA expression. Conclusions:Glioma patients with SMC4 mRNA high expression have poor prognosis. As a high risk factor, SMC4 mRNA can be used as an independent prognostic indicator of glioma patients, and its biological function is related to DNA replication of glioma.

The effect and underline mechanism of SMC4 on the proliferation, migration and invasion of human breast cancer cell MDA-MB-231 / 重庆医学

Objective To explore the effect of down-regulation of structural maintenance of chromosome 4 (SMC4) on proliferation,migration and invasion capability of human breast cancer cell line MDA-MB-231 and its possible mechanism.Methods The expressions of SMC4 in breast cancer tissues and the corresponding adjacent tissues from 20 patients with breast cancer were detected by qPCR.The expressions of SMC4 in human mammary epithelial cell line (MCF10A) and breast cancer cell lines (MDA-MB-231,T47D,SK-BR-3,MCF7 and MDA-MB-468) were detected by qPCR and western blot.After down-regulated the expression of SMC4 in MDA-MB-231 by small interfering RNA (siRNA),qPCR and western blot were used to determine the effect of transfection,CCK8 and clone formation assay were used to detect the proliferation and clonogenicity,Transwell chamber assay was used to detect the migration and invasion,and the possible pathway associated proteins were detected by western blot.Results The expression level of SMC4 in breast cancer tissues was higher than that in corresponding adjacent tissues (P＜0.05).The expression levels of SMC4 in breast cancer cell lines (MDA-MB-231,T47D,SK-BR-3,MCF7 and MDA-MB-468) were higher than that in MCF10A (P＜0.05).After successfully down-regulated SMC4 expression by siRNA,the proliferation,migration and invasion capability of MDA-MB-231 were significantly decreased (P＜0.05),and the expressions of pAKT and p-PI3K were significantly decreased (P＜0.05),whereas theexpressions of AKT and PI3K were not significantly affected.Conclusion Down-regulating the expression of SMCA can inhibit proliferation,migration and invasion capability of MDA-MP-231,which may be related to the activation of PI3K/AKT signaling pathway.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report / Insensibilidad al dolor en un niño con una deleción intersticial de novo del brazo largo del cromosoma 4

Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

One case of chromosome 4q21/22 deletion syndrome / 临床儿科杂志

Objective To enhance the understanding of clinical characteristics and genetic testing of chromosome 4q21/q22 deletion syndrome. Methods Chromosomal microarray analysis was used to detect genetic change in a child with special facial appearance and development delay. Results A 15.26-Mb deletion containing 76 geinges in chromosome 4q21.21q22.2 was identiifed. Thus, this girl was diagnosed as chromosome 4q21/q22 deletion syndrome. Conclusions Chromosome 4q21/q22 deletion syndrome has varied clinical manifestations including typical characteristics (such as absolute or relative macrocephaly, megalencephaly with a characteristic head shape and facial appearance, profound hypotonia, small hands and feet, short limbs, feeding difficulties), mental retardation/severe developmental delay, and other system abnormalities ( such as congenital heart disease, seizure, kidney cysts, etc). The diagnosis of chromosome 4q21/q22 deletion syndrome relies on chromosomal microarray analysis.

Wolf-Hirschhorn (4p-) Syndrome Presenting with Status Epilepticus / 대한간질학회지

Wolf-Hirschhorn syndrome is a well-recognized malformation syndrome with multiple congenital anomalies, resulting from partial deletion of the short arm of chromosome 4 (4p-). All affected individuals have intrauterine and postnatal growth retardation with marked feeding difficulties, developmental delay, and intellectual disability. Additionally, most of patients have seizures from early infancy. Although seizures are common with this syndrome, presenting with status epilepticus (SE) is rare. We report two cases of Wolf-Hirschhorn syndrome presenting with SE.

Wolf-Hirschhorn (4p-) Syndrome Presenting with Status Epilepticus

Wolf-Hirschhorn syndrome is a well-recognized malformation syndrome with multiple congenital anomalies, resulting from partial deletion of the short arm of chromosome 4 (4p-). All affected individuals have intrauterine and postnatal growth retardation with marked feeding difficulties, developmental delay, and intellectual disability. Additionally, most of patients have seizures from early infancy. Although seizures are common with this syndrome, presenting with status epilepticus (SE) is rare. We report two cases of Wolf-Hirschhorn syndrome presenting with SE.

Duplication of intrachromosomal insertion segments 4q32-->q35 confirmed by comparative genomic hybridization and fluorescent in situ hybridization / 대한생식의학회지

A 35-year-old man with infertility was referred for chromosomal analysis. In routine cytogenetic analysis, the patient was seen to have additional material of unknown origin on the terminal region of the short arm of chromosome 4. To determine the origin of the unknown material, we carried out high-resolution banding, comparative genomic hybridization (CGH), and FISH. CGH showed a gain of signal on the region of 4q32-->q35. FISH using whole chromosome painting and subtelomeric region probes for chromosome 4 confirmed the aberrant chromosome as an intrachromosomal insertion duplication of 4q32-->q35. Duplication often leads to some phenotypic abnormalities; however, our patient showed an almost normal phenotype except for congenital dysfunction in spermatogenesis.

Síndrome de Wolf-Hirschhorn (deleção do braço curto do cromossomo 4p): Relato de caso / Wolf-hirschhorn syndrome (terminal deletion of the short arm of chromosome 4p): case report

Objective: to report a case of Wolf-Hirschhorn Syndrome or partial deletion of the short arm of one chromosome 4 and present a brief literature review. Case Report: the authors report a case of a seven years-old child presenting the main findings of the syndrome: hypertelorism, big and large nose, prominent glabella, high arched eyebrows, antimongoloid palpebral fissures, bilateral low implantation of auricles, and microcephaly. Echodopplercardiographic study evidenced interatrial communication type ostium secundum without hemodynamic repercussion. Radiological examination showed clubfeet. The patient presents many cognitive deficits, mainly in functions as interaction and learning. Evident motor dysfunctions compromising gait and also muscle atrophy. The child also presented convulsive crises in the first year of life that are currently controlled by the use of anticonvulsants. Final considerations: the incidence of the Wolf-Hirschhorn Syndrome is rare, with only 100 cases reported until1981. The prognosis is relative, with one third of the patients dying with in the first year, while other children are alive with more than twelve years of age. This case was diagnosed based on clinical, radiological, echodopplercardiographical criteria and confirmed by the karyotype's result 46,XX,del(4)(p15?1).

Objetivo: descrever um caso de síndrome de Wolf-Hirschhorn ou deleção parcial terminal do braço curto de um dos cromossomos 4 e apresentar uma breve revisão da literatura. Relato de Caso: criança de sete anos que apresenta os principais aspectos da síndrome: hipertelorismo, nariz grande e adunco, glabela proeminente, fissuras palpebrais antimongolóides, implantação baixa dos pavilhões auriculares, micrognatia e microcefalia. Radiografias do esqueleto revelaram má formação óssea, causando pés eqüinovaros. A ecodopplercardiografia evidenciou CIA sem repercussão hemodinâmica. A paciente apresenta inúmeros déficits cognitivos, fundamentalmente nas funções de interação e aprendizado, além dos distúrbios motores evidentes, com comprometimento da marcha e atrofia muscular; crises convulsivas no primeiro ano de vida, mas que estão atualmente controladas pelo uso de anticonvulsivante. Considerações Finais: a incidência da Síndrome de Wolh-Hirschhorn é rara, com 100 casos publicados até 1981. O prognóstico é relativo, com 1/3 dos pacientes morrendo no decorrer do primeiro ano, enquanto outras crianças estão vivas com mais de 12 anos. O caso apresentado foi diagnosticado com base em critérios clínicos, radiológicos, ecodopplercardiogáficos e confirmado pelo resultado do cariótipo: 46,XX,del(4)(p15?1).

Identification of Tumor Suppressor Loci on the Long Arm of Chromosome 4 in Primary Small Cell Lung Cancers

Recent cytogenetic studies have indicated that loss of the long arm of chromosome 4 is a frequent event in small cell lung cancer (SCLC), which suggests the presence of tumor suppressor genes there. To precisely map tumor-suppressor loci on chromosome 4q for further positional cloning efforts, we tested 15 primary SCLCs. Forty two polymorphic microsatellite markers located on chromosome 4q were used in the microsatellite analysis. We found that 12 (80%) of the 15 tumors exhibited loss of heterozygosity (LOH) in at least one of the tested microsatellite markers, and that 3 (25%) of these 12 tumors exhibited a larger area of deletion on chromosome 4q. Frequent LOH, defined as occurring in more than 50% of the tumors, was observed in five commonly deleted regions on 4q, namely 4q24, 4q27-28.3, 4q33, 4q34.1, and 4q34.3-35.2. Of these 5, LOH at 4q33 was the most frequent (61.5%). Six (40%) of the 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. Shifted bands occurred in 3.7% (23 of 630) of the loci tested. Our data demonstrated that at least five tumor-suppressor loci exist on the long arm of chromosome 4 and that they may play an important role in the development and progression of primary small cell lung cancer tumorigenesis.

A Case of 4q Deletion with Partial Agenesis of Corpus Callosum

Syndrome of 4q deletion is characterized by an abnormal shape of the skull, craniofacial dysmorphism, cardiovascular malformations, genitourinary defects, limb and digital anomalies, and developmental delay. We experienced a case of 4q interstitial deletion in a 2 day-old female neonate who showed short extremities, partial agenesis of corpus callosum and congenital heart defects. We report the case with a brief review of the literature.

A Case of Wolf-Hirschhorn Syndrome with Long Term Survival Diagnosed by Fluorescent In-situ Hybridization (FISH)

Wolf-Hirschhorn syndrome is a multiple malformation syndrome associated with mental and developmental retardation, resulting from a deletion at the short arm of chromosome 4 (4p16.3). We report a 11-year-old girl with Wolf-Hirschhorn syndrome, who was presented with severe growth and mental retardation along with characteristic features-frontal bossing, hypertelorism, downslanting of the palpebral fissures and fishlike lips. The diagnosis was confirmed by fluorescent in-situ hybridization (FISH).

A Case of Wolf-Hirschhorn Syndrome with Long Term Survival Diagnosed by Fluorescent In-situ Hybridization (FISH)

Wolf-Hirschhorn syndrome is a multiple malformation syndrome associated with mental and developmental retardation, resulting from a deletion at the short arm of chromosome 4 (4p16.3). We report a 11-year-old girl with Wolf-Hirschhorn syndrome, who was presented with severe growth and mental retardation along with characteristic features-frontal bossing, hypertelorism, downslanting of the palpebral fissures and fishlike lips. The diagnosis was confirmed by fluorescent in-situ hybridization (FISH).

Prenatal Diagnosis of the Wolf-Hirschhorn Syndrome

Wolf-Hirschhorn syndrome (WHS) is caused by a deletion of the short arm on chromosome 4 and is characterized by multiple congenital abnormalities, growth and mental retardation. In this case report, we performed amniocentesis for the chromosome analysis on a 25-year-old pregnant woman at 16 weeks of gestation whom we suspected of Edward's syndrome by the triple test of maternal serum and ultrasonography. The result of analysis revealed a karyotype of the fetus with 46,XY,del(4)(p15) by trypsin Giemsa's banding technique. With the result, we were able to diagnose the fetus as having WHS. As such, after therapeutic termination of the pregnancy, we confirmed WHS through the sampling of tissue by both trypsin Giemsa's banding and fluorescence in situ hybridization (FISH) method. To determine the origin of the WHS, we further tested the karyotypes of the parents. As parental karyotypes were found to be normal, we determined the case of the fetal WHS to be de novo.