Genetics research最新文献

Glioma represents the most prevalent intracranial neoplasms. Lower-grade gliomas (LGGs) are an important subtype of glioma, but the risk stratification of LGG has not been fully elucidated. As a recently recognized form of programmed cell death, cuproptosis is intimately tied to mitochondrial metabolism. Moreover, investigations have revealed that cuproptosis has been implicated in tumor initiation and progression. Long noncoding RNAs (lncRNAs) are engaged in diverse biological processes and connected with the malignant phenotype of gliomas. However, the significance of cuproptosis-related lncRNAs (CRLs) in LGG development remains not fully elucidated. In this work, 963 CRLs were identified using correlation analysis, and a prognostic signature was constructed based on LASSO and multivariate Cox regression analyses. This signature comprised four CRLs: AC002456.1, tumor protein p63 regulated 1-antisense RNA 1 (TPRG1-AS1), AC098851.1, and LYR motif containing 4-antisense RNA 1 (LYRM4-AS1). According to the CRL-based signature, LGG patients were classified into distinct risk groups. To investigate the involvement of biological processes in each LGG sample, we performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) comparing the different risk stratifications. Subsequently, the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data and the tumor immune dysfunction and exclusion (TIDE) were utilized to access the tumor immune landscape of LGG samples. The results demonstrated that the immune landscapes of different risk stratifications differed significantly. Furthermore, we explored the association between the CRL risk signature and immunotherapy effectiveness using the IMvigor210 dataset. Several prospective drugs targeting samples with high scores were predicted, namely, MG-132, PLX-4720, AZD6482, and BMS-536924. We verified the antiglioma effect of MG-132 in vitro. Moreover, experiments conducted in vitro demonstrated that knockdown of the expression of the CRLs TPRG1-AS1 and LYRM4-AS1 might impair the migration and proliferation capacity of glioma cells. Taken together, these results indicate that CRLs are linked to prognosis and immune characteristics in LGG and give innovative therapeutic methods for individuals with LGG across different risk stratifications.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from different molecular mechanisms. Investigating the correlation between genotypes and phenotypes is crucial to facilitate accurate diagnosis and effective prevention strategies for this disorder. However, determining the genotypes of patients to analyze genotype‒phenotype correlations is challenging when parental genetic information is lacking. Therefore, we proposed a genotyping strategy for use with 11 unrelated Chinese patients with AS who were recruited for this study. The strategy involved a combination of methylation-specific polymerase chain reaction (MS-PCR), exome sequencing (ES), Sanger sequencing, and MS multiplexed ligation probe amplification (MS-MLPA). The results revealed that the number of molecular deletions involving the critical 15q11. 2-q13 region (54.5%) was lower than that reported in other studies of Chinese patients. In addition, the prevalence of patients with imprinting defects (IDs) (27.3%) and variants (18.2%) was greater, whereas the proportion of patients with uniparental disomy (UPDs) was lower. We also summarized the characteristics of patients with different genotypes and analyzed the correlations between genotypes and phenotypes. Compared with the consensus for diagnostic criteria, our results showed that several features were less common, including the combination of frequent laughing/smiling, tremulous limb movements, ataxia of gait, and microcephaly. Conversely, the incidence of both epilepsy and abnormal electroencephalograms (EEGs) was greater. Notably, a novel mutation in the UBE3A gene that had not been previously reported was identified in a family.

Background: Temperature sensitivity has gained considerable attention in the era of precision medicine. This trait has long been used to identify cold-heat patterns (C-HPs), a diagnostic framework in Traditional Korean Medicine that categorizes individuals based on their thermal responses. C-HP helps understand an individual's inherent physical characteristics, which have been shown to be highly heritable and thus shaped by genetic factors. However, genetic markers that are significantly associated with this trait remain scarce. To address this gap, we aimed to identify candidate single-nucleotide polymorphisms (SNPs) based on previous genomewide association studies (GWASs) of related traits.

Methods: Given the limited research directly addressing C-HP, we incorporated genetic studies related to traits such as "Cold" or "Heat," as well as thyroid hormone, which plays a key role in thermogenesis through the activation of various metabolic pathways. After selecting the SNPs reported in previous GWAS from the GWAS Catalog (EMBL-EBI), we validated these findings using 90 Korean patients reporting C-HP, with statistical significance assessed through residual permutations. Gene set enrichment analysis (GSEA) was performed using the GO Biological Process 2023 dataset to identify the pathways associated with C-HP. Furthermore, we compared our findings with control traits in order to confirm that the observed associations were specific to C-HP-related traits rather than random correlations. Principal component analysis (PCA) was conducted on candidate SNPs from the 1000 Genomes reference dataset to illustrate the ethnic variation for C-HP across five populations.

Results: Of 63 GWAS, we selected 548 SNPs for validation. Ultimately, 20 candidate SNPs associated with heat patterns and 19 candidate SNPs associated with cold patterns were identified. Of the heat-pattern SNPs, 18 were linked to thyroid hormone traits, with key SNPs including rs12409301 (CAPZB) and rs12855 (CDKN2C). For the cold-pattern trait, 16 SNPs were associated with thyroid hormones such as rs622474 (PDE4B) and rs11204752 (GOLPH3L). GSEA confirmed notable enrichment in vascular processes for the heat pattern and mitochondrial organization for the cold pattern. The most significant pathway was vascular smooth muscle cell development (p value = 1.28 × 10^-5) in the heat pattern. The clear ethnic differences in C-HP were observed in the PCA of 1000 Genomes populations where East Asian and African populations formed distinct, well-separated clusters.

Conclusion: Our study suggested a total of 39 candidate SNPs as genetic markers for C-HP that are plausible in the context of temperature sensitivity. We hope that our findings will provide a valuable basis for further biological research and potential clinical applications of C-HP.

Background: Gastric cancer poses a substantial public health burden, with rising mortality rates in metastatic stages. Elucidating the molecular mechanisms underlying lymph node metastasis is critical for developing novel therapeutic interventions. Methods: Using data from the Cancer Genome Atlas (TCGA), we stratified gastric cancer patients by lymph node metastasis stage (N0-N3) to identify key molecular determinants of metastatic progression. Integrated bioinformatic analyses included differential gene expression profiling, protein-protein interaction networks, survival analysis, and immune microenvironment characterization, with a focused investigation of THPO. Results: We identified metastasis-associated genes, notably THPO, which exhibited stage-dependent upregulation in advanced lymph node metastasis (N3). Elevated THPO expression correlated significantly with adverse prognostic outcomes, including reduced overall survival, disease-free survival, and progression-free survival (all p < 0.05). Mechanistically, THPO promoted epithelial-mesenchymal transition and showed a positive correlation with M2 macrophage infiltration, implicating it in tumor progression. Furthermore, a THPO-centric prognostic signature demonstrated high accuracy in predicting 1-, 3-, and 5-year survival rates (AUC > 0.80), supporting its clinical utility. Furthermore, THPO knockdown in MKN-45 cells suppressed migration and blunted the EMT pathway, confirming its prometastatic role in gastric cancer. Conclusion: Our findings establish THPO as a promising biomarker and therapeutic target in gastric cancer. Molecular insights into lymph node metastasis may facilitate the development of precision prognostic tools and tailored therapeutic strategies, highlighting the imperative for further mechanistic and translational studies.

[This corrects the article DOI: 10.1155/genr/2340176.].

Breast cancer ranks among the top causes of cancer-related deaths in women around the globe, with genetic mutations in the BRCA1 gene being a frequent cause of breast or ovarian cancer. This study investigates hotspot mutations in exon 11 of the BRCA1 gene among Pakistani women diagnosed with breast cancer. Thirty clinically diagnosed breast cancer patients, all women, were enrolled in the current study, and high-quality DNA was extracted from peripheral blood samples. Two of the twenty-five successfully sequenced samples had a homozygous missense variant (c.2312T > C: p.Leu771Ser) detected by Sanger sequencing after PCR amplification. Upon investigation in the ClinVar database, the identified variant showed conflicting interpretations of pathogenicity. Demographic data highlighted an early disease onset, showing that 56% of patients were under 50 years of age. The need for genetic screening was further supported by the fact that 24% of the patients had a positive family history of cancer. Our study emphasizes the necessity of screening BRCA1 gene mutations to better understand the pathogenic potential of the identified variants in the Pakistani population.

Background: Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related mortality worldwide. However, the expression and role of TIPE3 and RAC1 in LUAD are not well characterized. Objective: This study aimed to investigate the expression and clinicopathological significance of TNFAIP8L3 (TIPE3) and RAC1 in LUAD, as well as the relationship between these two proteins. Methods: Immunohistochemistry (IHC) was utilized to detect the expression of TIPE3 and RAC1 in tumor and adjacent normal tissues from 183 LUAD patients. A comprehensive analysis of clinicopathological data and subsequent follow-up outcomes was conducted in relation to TIPE3 and RAC1 expression levels. The correlation between these two proteins was also evaluated. Results: Both TIPE3 and RAC1 expression were upregulated in tumor tissues of LUAD. TIPE3 expression was significantly associated with advanced T stage (p=0.001), N stage (p=0.005), and TNM stage (p=0.001). Similarly, increased RAC1 expression was also associated with advanced T stage (p=0.003), N stage (p=0.003), and TNM stage (p=0.001). Kaplan-Meier survival analysis and Cox regression modeling demonstrated that increased TIPE3 and RAC1 expression were independent prognostic factors for poor outcomes in LUAD. Furthermore, Spearman correlation analysis revealed a positive association between TIPE3 and RAC1 expression (r = 0.305, p < 0.001). Combined expression of TIPE3 and RAC1 improved risk stratification and prognostic prediction in LUAD. Conclusion: TIPE3 and RAC1 serve as potential biomarkers of tumor progression and poor prognosis in LUAD, offering promising targets for future therapeutic interventions.

49, XXXYY is a rare form of sex chromosomal aneuploidy that has been reported in 11 cases worldwide. The parental origin of the extra sex chromosomes and the specific clinical features of this condition remain unclear. We recruited a case with 49, XXXYY and performed genome-wide copy number variation analysis using next-generation sequencing. In addition, the parental origin of the extra sex chromosomes was determined through short tandem repeats (STRs) locus genotyping. Furthermore, a comprehensive review and comparison of clinical phenotypes were conducted among 12 cases with 49, XXXYY. The patient exhibited a karyotype of 49, XXXYY without any mosaic patterns. No pathogenic microdeletions or microduplications (> 100 kb) were identified in autosomes 1-22. Analysis of the STR loci revealed that two of three X chromosomes originated from father. This suggests that the nondisjunction of chromosomes X and Y during stages I and II of meiotic spermatogenesis led to the production of an abnormal sperm with XXYY. Subsequently, fertilization of a normal oocyte with this abnormal sperm resulted in an abnormal zygote with pentasomy XXXYY. The main clinical features observed in these cases included varying degrees of mental retardation, minor facial dysmorphology, and gonadal or endocrine abnormalities. In conclusion, 49, XXXYY is a rare chromosomal disorder characterized by mental retardation and facial dysmorphology. Nondisjunction of chromosomes X and Y during stages I and II of meiotic spermatogenesis is a critical factor contributing to the development of this abnormal karyotype.

Background: A growing number of studies are exploring the association between HOTAIR rs920778 polymorphisms and cancer risk, but to date, there has been controversy and uncertainty. Preliminary evidence suggests that this polymorphism may influence cancer susceptibility, particularly in Asian populations and specific cancer types such as cervical cancer (CC) and breast cancer (BC). We therefore conducted an updated meta-analysis to accurately assess the association of the HOTAIR rs920778 polymorphism with cancer risk. Method: Comprehensive literature searches were performed in PubMed, Embase, and Web of Science up to September 8, 2023. Inclusion criteria included case-control studies with allele frequency data for both cases and controls. A total of 29 case-control studies were selected for quantitative analysis. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Stata software (Version 11) to evaluate the association between the rs920778 polymorphism and cancer risk. Heterogeneity and publication bias were assessed using chi-square tests, I ² statistics, and funnel plots with Egger's test. Results: Our analysis of the results found a significant association between the rs920778 polymorphism and cancer susceptibility. In Asian populations, all five genetic models of the rs920778 polymorphism have been shown to increase overall cancer susceptibility. At the same time, we performed stratified analyses based on cancer type and found that all genetic models revealed significantly increased susceptibility to CC in Asian populations. Conversely, the heterozygote model of rs920778 demonstrated significantly reduced susceptibility to BC, with consistent effects across racial groups. Conclusions: Our meta-analysis demonstrated that the HOTAIR rs920778 polymorphism may be a risk factor for cancer but may serve as a protective factor for BC. Future studies require larger sample sizes and gene function analysis, suggesting that the rs920778 polymorphism could serve as a genetic biomarker to guide targeted therapies or cancer screening.

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental conditions with complex genetic etiologies. Recent advances in whole exome sequencing (WES) have enabled comprehensive detection of clinically relevant variants, particularly single-nucleotide variations (SNVs) and InDels, in ASD genetic diagnostics. Here, we performed WES on 50 Chinese children with ASD who tested negative for copy number variants (CNVs). The analysis achieved a diagnostic yield of 10% (5/50 cases). All SNVs and InDels were loss-of-function (LOF) and were slightly more frequent among females (male vs. female: 9.3% vs. 14.3%). A total of five causative genes (PRODH9, PTEN, DEPDC5, SATB2, and CYFIP1) were identified in this study. Variants in ASD-associated genes (CHD8, FOXP1, and SHANK1) and genes linked to other neurodevelopmental disorders (CDH15, GATAD2B, and SHROOM4) were also detected. Despite the small sample size, our findings contribute partially to the dataset on the phenotype and genetic etiology of ASD and underscore WES as a critical tool for elucidating genetic etiologies in CNV-negative ASD cohorts.