In peripheral blood, cell‐free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which indicates molecular abnormalities in metastatic breast tumor tissue. The sequencing of cfDNA of Metastatic ...Breast Cancer (MBC) patients allows assessment of therapy response and noninvasive treatment. In the proposed study, clinically significant alterations in PIK3CA and TP53 genes associated with MBC resulting in a missense substitution of His1047Arg and Arg282Trp from an next‐generation sequencing‐based multi‐gene panel were reported in a cfDNA of a patient with MBC. To investigate the impact of the reported mutation, we used molecular docking, molecular dynamics simulation, network analysis, and pathway analysis. Molecular Docking analysis determined the distinct binding pattern revealing H1047R‐ATP complex has a higher number of Hydrogen bonds (H‐bonds) and binding affinity with a slight difference compared to the PIK3CA‐ATP complex. Following, molecular dynamics simulation for 200 ns, of which H1047R‐ATP complex resulted in the instability of PIK3CA. Similarly, for TP53 mutant R282W, the zinc‐free state (apo) and zinc‐bounded (holo) complexes were investigated for conformational change between apo and holo complexes, of which the holo complex mutant R282W was unstable. To validate the conformational change of PIK3CA and TP53, 80% mutation of H1047R in the kinase domain of p110α expressed ubiquitously in PIK3CA protein that alters PI3K pathway, while R282W mutation in DNA binding helix (H2) region of P53 protein inhibits the transcription factor in P53 pathway causing MBC. According to our findings, the extrinsic (hypoxia, oxidative stress, and acidosis); intrinsic factors (MYC amplification) in PIK3CA and TP53 mutations will provide potential insights for developing novel therapeutic methods for MBC therapy.
Circular RNAs (circRNAs) are regulatory elements that are involved in orchestrating gene expression and protein functions and are implicated in various biological processes including cancer. Notably, ...breast cancer has a significant mortality rate and is one of the most common malignancies in women. CircRNAs have been demonstrated to contribute to the pathogenesis of breast cancer including its initiation, progression, metastasis, and resistance to drugs. By acting as miRNA sponges, circRNAs can indirectly influence gene expression by disrupting miRNA regulation of their target genes, ultimately altering the course of cancer development and progression. Additionally, circRNAs can interact with proteins and modulate their functions including signaling pathways involved in the initiation and development of cancer. Recently, circRNAs can encode peptides that play a role in the pathophysiology of breast cancer and other diseases and their potential as diagnostic biomarkers and therapeutic targets for various cancers including breast cancer. CircRNAs possess biomarkers that differentiate, such as stability, specificity, and sensitivity, and can be detected in several biological specimens such as blood, saliva, and urine. Moreover, circRNAs play an important role in various cellular processes including cell proliferation, differentiation, and apoptosis, all of which are integral factors in the development and progression of cancer. This review synthesizes the functions of circRNAs in breast cancer, scrutinizing their contributions to the onset and evolution of the disease through their interactions with exosomes and cancer-related intracellular pathways. It also delves into the potential use of circRNA as a biomarker and therapeutic target against breast cancer. It discusses various databases and online tools that offer crucial circRNA information and regulatory networks. Lastly, the challenges and prospects of utilizing circRNAs in clinical settings associated with breast cancer are explored.
Zinc fingers represent a highly diverse structural domain, with P53 being a notable example among zinc-dependent transcription factors. The folding patterns of proteins in the cell are heavily ...influenced by the concentration of zinc. The potential for zinc loss arises due to its dysregulation and the frequent occurrence of tumorigenic P53 mutations. This could lead to significant consequences such as protein misfolding and a reduction in tumor-suppressing capabilities. To gain deeper insights into the structural conformation, stability, flexibility, and compactness of the zinc-binding mutation C176F, a comprehensive comparative computational analysis was conducted on the wildtype (WT) and mutant (MT) P53 in the presence (Holo) and absence (Apo) of zinc. This analysis was performed using molecular dynamic simulation. The overall observation was that the mutation in C176F reduces the metal binding affinity and results in less stability in the Apo and Holo P53 MT protein.
Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC accounts for 84% of all lung cancer cases. In recent years, advances in pathway understanding, methods for discovering ...novel genetic biomarkers, and new drugs designed to inhibit the signaling cascades have enabled clinicians to personalize therapy for NSCLC.
The primary aim of this study is to identify the genes associated with NSCLC that harbor pathogenic variants that could be causative for NSCLC. The second aim is to investigate their roles in different pathways that lead to NSCLC.
We examined exome-sequencing datasets from 54 NSCLC patients to characterize the variants associated with NSCLC.
Our findings revealed that 17 variants in 14 genes were considered highly pathogenic, including CDKN2A, ERBB2, FOXP1, IDH1, JAK3, KMT2D, K-Ras, MSH3, MSH6, POLE, RNF43, TCF7L2, TP53, and TSC1. Gene set enrichment analysis revealed the involvement of transmembrane receptor protein tyrosine kinase activity, protein binding, ATP binding, phosphatidylinositol-4,5-bisphosphate 3-kinase, and Ras guanyl-nucleotide exchange factor activity. Pathway analysis of these genes yielded different cancer-related pathways, including colorectal, prostate, endometrial, pancreatic, PI3K-Akt signaling pathways, and signaling pathways regulating pluripotency of stem cells. Module 1 from protein-protein interactions (PPIs) identified genes that harbor pathogenic SNPs. Three of the most deleterious SNPs are ERBB2 (rs1196929947), K-Ras (rs121913529), and POLE (rs751425952). Interestingly, one patient has a pathogenic K-Ras variant (rs121913529) co-occurred with the missense variant (rs752054698) inTSC1 gene.
This study maps highly pathogenic variants associated with NSCLC and investigates their contributions to the pathogenesis of NSCLC. This study sheds light on the potential applications of precision medicine in patients with NSCLC.
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•In this study, we identified highly pathogenic variants and explored their roles in NSCLC development and proliferation.•Our findings revealed that 17 nsSNPs located in 14 genes were considered highly pathogenic mutation.•WES analysis also revealed that pathogenic K-Ras mutation G12V co-occurred with the missense (Y704C) from TSC1.
Genome‐wide association studies (GWAS) have identified an association between polymorphisms in the FTO gene and obesity. The FTO: rs9939609, an intronic variant, is considered a risk allele for ...developing diabesity in homozygous and heterozygous forms. This study aimed to investigate the molecular structure of the available inhibitors specific to the FTO mutations along with the rs9939609 variant. We identified the best‐suited inhibitor molecules for each mutant type containing the rs9939609 risk allele. Missense mutations unique to obesity and containing the risk allele of rs9939609 were retrieved from dbSNP for this study. Further stability testing for the mutations were carried out using DynaMut and iStable tools. Three mutations (G187A, M223V, and I492V) were highly destabilizing the FTO structure. These three mutants and native FTO were docked with each of the nine‐inhibitor molecules collected from literature studies with the help of PyRx and AutoDock. Further structural behavior of the mutants and native FTO were identified with molecular dynamics simulations and MM‐PBSA analyses, along with the 19complex inhibitor compound. We found the compound 19complex exhibited better binding interactions and is the top candidate inhibitor for the M223V and I492V mutants. This study provided insights into the structural changes caused due to mutations in FTO, and the binding mechanism of the inhibitor molecules. It could aid in developing antiobesity drugs for treating patients with mutations and risk alleles predisposing to obesity.
The FTO: rs9939609, an intronic variant, is considered a risk allele, in both homozygous and heterozygous forms, for developing diabesity. This study identified the best‐suited inhibitor molecule for each mutant type containing the rs9939609 risk allele. Our study identified 19complex is the best‐suited inhibitor for the native M223V and I492V FTO mutants.
Over the past decade, conventional lab work strategies have gradually shifted from being limited to a laboratory setting towards a bioinformatics era to help manage and process the vast amounts of ...data generated by omics technologies. The present work outlines the latest contributions of bioinformatics in analyzing microarray data and their application to cancer. We dissect different microarray platforms and their use in gene expression in cancer models. We highlight how computational advances empowered the microarray technology in gene expression analysis. The study on protein-protein interaction databases classified into primary, derived, meta-database, and prediction databases describes the strategies to curate and predict novel interaction networks in silico. In addition, we summarize the areas of bioinformatics where neural graph networks are currently being used, such as protein functions, protein interaction prediction, and in silico drug discovery and development. We also discuss the role of deep learning as a potential tool in the prognosis, diagnosis, and treatment of cancer. Integrating these resources efficiently, practically, and ethically is likely to be the most challenging task for the healthcare industry over the next decade; however, we believe that it is achievable in the long term.
