METHODS: Transcriptomic and clinical data pertaining to LUAD were retrieved from open-access databases to establish an association between mRNA expression profiles and the presence of TDP-43. A risk-prognosis model was developed to compare patient survival rates across various groups, and its accuracy was also assessed. Additionally, differences in tumor stemness, mutational profiles, tumor microenvironment (TME) characteristics, immune checkpoints, and immune cell infiltration were analyzed in the different groups. Moreover, the study entailed predicting the potential response to immunotherapy as well as the sensitivity to commonly employed chemotherapeutic agents and targeted drugs for each distinct group.
RESULTS: The TDP-43 Co-expressed Gene Risk Score (TCGRS) model was constructed utilizing four genes: Kinesin Family Member 20A (KIF20A), WD Repeat Domain 4 (WDR4), Proline Rich 11 (PRR11), and Glia Maturation Factor Gamma (GMFG). The value of this model in predicting LUAD patient survival is effectively illustrated by both the Kaplan-Meier (K-M) survival curve and the area under the receiver operating characteristic curve (AUC-ROC). The Gene Set Enrichment Analysis (GSEA) revealed that the high TCGRS group was primarily enriched in biological pathways and functions linked to DNA replication and cell cycle; the low TCGRS group showed primary enrichment in immune-related pathways and functions. The high and low TCGRS groups showed differences in tumor stemness, mutational burden, TME, immune infiltration level, and immune checkpoints. The predictions analysis of immunotherapy indicates that the Tumor Immune Dysfunction and Exclusion (TIDE) score (p
METHODS: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively.
RESULTS: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia.
CONCLUSION: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.
MATERIALS AND METHODS: We selected 157 NPC cases and 136 controls from two hospitals in Kuala Lumpur, Malaysia for this study. The polymorphisms studied were genotyped by PCR-RFLP assay and allele and genotype frequencies, haplotype and linkage disequilibrium were determined using SNPstat software.
RESULTS: For the XPD Lys751Gln polymorphism, the frequency of the Lys allele was higher in cases than in controls (94.5% versus 85.0%). For the XRCC1 Arg280His polymorphism, the frequency of Arg allele was 90.0% and 89.0% in cases and controls, respectively and for XRCC1 Arg399Gln the frequency of the Arg allele was 72.0% and 72.8% in cases and controls respectively. All three polymorphisms were in linkage disequilibrium. The odds ratio from haplotype analysis for these three polymorphisms and their association with NPC was 1.93 (95%CI: 0.90-4.16) for haplotype CGC vs AGC allele combinations. The global haplotype association with NPC gave a p-value of 0.054.
CONCLUSIONS: Our study provides an estimate of allele and genotype frequencies of XRCC1Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in the Malaysian population and showed no association with nasopharyngeal cancer.
PATIENTS AND METHODS: We report two siblings of a healthy but consanguineous Malaysian family presenting with severe short stature caused by CPHD with a variable phenotype. Importantly, at the beginning the girl presented with isolated GHD, whereas the boy was hypothyroid. As the most common gene alterations responsible for CPHD are within either the PROP-1- or the POU1F1- (PIT-1)-gene these two genes were further studied.
RESULTS: Subsequent sequencing of the six exons of the POU1F1-gene allowed the identification of a new N-terminal mutation (Q4ter) in these two children. A substitution of C to T induced a change from a glutamine (CAA) to a stop codon (TAA) in exon 1 of the PIT-1 protein. Both affected children were homozygous for the mutation, whereas the mother and father were heterozygous.
CONCLUSION: We describe two children with autosomal recessive inherited CPHD caused by a new N-terminal located mutation within the PUO1F1-gene. The clinical history of these two children underline the phenotypic variability and support the fact that children with any isolated and/or combined PHD need to be closely followed as at an any time other hormonal deficiencies may occur. In addition, molecular analysis of the possible genes involved might be most helpful for the future follow-up.
METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
MATERIALS AND METHODS: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction- restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing.
RESULTS: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects ≥50 years and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC.
CONCLUSIONS: Our findings suggest that inheritance of variant alleles in XRCC1 Arg194Trp and Arg399Gln SNPs may act as biomarkers for the early detection of GIC, especially for gastric and colorectal cancers in the Sabah population.
MATERIALS AND METHODS: Genomic DNA was isolated from peripheral blood of 71 breast cancer patients and 260 healthy controls and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
RESULTS: Our study showed that the c1/c2 genotype or subjects with at least one c2 allele in CYP2E1 rs3813867 SNP had significantly increased almost 1.8-fold higher breast cancer risk in Malaysian women overall. In addition, the variant Phe allele in STK15 rs2273535 SNP appeared to protect against breast cancer in Malaysian Chinese. No significance association was found between XRCC1 SNPs and breast cancer risk in the population.
CONCLUSIONS: This study provides additional knowledge on CYP2E1, STK15 and XRCC1 SNP impact of risk of breast cancer, particularly in the Malaysian population. From our findings, we also recommend Malaysian women to perform breast cancer screening before 50 years of age.
RESULTS: In this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer's disease; 2. ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors.
CONCLUSION: By merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.