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Background: Colorectal cancer (CRC) is the leading cancer among Saudis, and mutations in BRAF , KRAS , and NRAS genes are therapeutically significant due to their association with pathways critical for cell cycle regulation. This study evaluates the prevalence and frequency of somatic mutations in these actionable genes in Saudi CRC patients and assesses their pathogenicity with bioinformatics methods. Methodology: The study employed the TruSight Tumor 15 next-generation sequencing (NGS) panel on 86 colorectal cancer (CRC) samples to detect somatic mutations in BRAF , KRAS , and NRAS genes. Bioinformatic analyses of NGS sequences included variant annotation with ANNOVAR, pathogenicity prediction, variant reclassification with CancerVar, and extensive structural analysis. Additionally, molecular docking assessed the binding of Encorafenib to wild-type and mutant BRAF proteins, providing insights into the therapeutic relevance of pathogenic variants. Results: Out of 86 tumor samples, 40 (46.5%) harbored somatic mutations within actionable genes (BRAF : 2.3%, KRAS : 43%, NRAS : 2.3%). Fourteen missense variants were identified (BRAF : n = 1, KRAS : n = 11, NRAS : n = 2). Variants with strong clinical significance included BRAF V600E (2.32%) and KRAS G12D (18.60%). Variants with potential clinical significance included several KRAS and an NRAS mutation, while variants of unknown significance included KRAS E49K and NRAS R102Q. One variant was novel: NRAS R102Q, and two were rare: KRAS E49K and G138E. We further extended the CancerVar prediction capability by adding new pathogenicity prediction tools. Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart. Conclusion: Overall, this study highlights the importance of comprehensive molecular screening and bioinformatics in understanding the mutational landscape of CRC in the Saudi population, ultimately improving targeted drug treatments. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a globally underdiagnosed genetic condition associated with premature cardiovascular death. The genetic etiology data on Arab FH patients is scarce. Therefore, this study aimed to identify the genetic basis of FH in a Saudi family using whole exome sequencing (WES) and multidimensional bioinformatic analysis. Our WES findings revealed a rare heterozygous gain-of-function variant (R496W) in the exon 9 of the PCSK9 gene as a causal factor for FH in this family. This variant was absent in healthy relatives of the proband and 200 healthy normolipidemic controls from Saudi Arabia. Furthermore, this variant has not been previously reported in various regional and global population genomic variant databases. Interestingly, this variant is classified as “likely pathogenic" (PP5) based on the variant interpretation guidelines of the American College of Medical Genetics (ACMG). Computational functional characterization suggested that this variant could destabilize the native PCSK9 protein and alter its secondary and tertiary structural features. In addition, this variant was predicted to negatively influence its ligand-binding ability with LDLR and Alirocumab antibody molecules. This rare PCSK9 (R496W) variant is likely to expand our understanding of the genetic basis of FH in Saudi Arabia. This study also provides computational structural insights into the genotype-protein phenotype relationship of PCSK9 pathogenic variants and contributes to the development of personalized medicine for FH patients in the future. [ABSTRACT FROM AUTHOR]

Paget's disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget's disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research. [ABSTRACT FROM AUTHOR]

Paget's disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget's disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is a urogenital cancer affecting millions of post-menopausal women, globally. This study aims to identify key miRNAs, target genes, and drug targets associated with EC metastasis. The global miRNA and mRNA expression datasets of endometrial tissue biopsies (24 tumors +3 healthy tissues for mRNA and 18 tumor +4 healthy tissues for miRNAs), were extensively analyzed by mapping of DEGs, DEMi, biological pathway enrichment, miRNA-mRNA networking, drug target identification, and survival curve output for differentially expressed genes. Our results reveal the dysregulated expression of 26 miRNAs and their 66 target genes involved in focal adhesions, p53 signaling pathway, ECM-receptor interaction, Hedgehog signaling pathway, fat digestion and absorption, glioma as well as retinol metabolism involved in cell growth, migration, and proliferation of endometrial cancer cells. The subsequent miRNA-mRNA network and expression status analysis have narrowed down to 2 hub miRNAs (hsa-mir-200a, hsa-mir-429) and 6 hub genes (PTCH1, FOSB, PDGFRA, CCND2, ABL1, ALDH1A1). Further investigations with different systems biology methods have prioritized ALDH1A1, ABL1 and CCND2 as potential genes involved in endometrial cancer metastasis owing to their high mutation load and expression status. Interestingly, overexpression of PTCH1, ABL1 and FOSB genes are reported to be associated with a low survival rate among cancer patients. The upregulated hsa-mir-200a-b is associated with the decreased expression of the PTCH1, CCND2, PDGFRA, FOSB and ABL1 genes in endometrial cancer tissue while hsa-mir-429 is correlated with the decreased expression of the ALDH1A1 gene, besides some antibodies, PROTACs and inhibitory molecules. In conclusion, this study identified key miRNAs (hsa-mir-200a, hsa-mir-429) and target genes ALDH1A1, ABL1 and CCND2 as potential biomarkers for metastatic endometrial cancers from large-scale gene expression data using systems biology approaches. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) is a fatally aggressive urogenital cancer killing millions of men, globally. Thus, this study aims to identify key miRNAs, target genes, and drug targets associated with prostate cancer metastasis. Methods: The miRNA and mRNA expression datasets of 148 prostate tissue biopsies (39 tumours and 109 normal tissues), were analysed by differential gene expression analysis, protein interactome mapping, biological pathway analysis, miRNA-mRNA networking, drug target analysis, and survival curve analysis. Results: The dysregulated expression of 53 miRNAs and their 250 target genes involved in Hedgehog, ErbB, and cAMP signalling pathways connected to cell growth, migration, and proliferation of prostate cancer cells was detected. The subsequent miRNA-mRNA network and expression status analysis have helped us in narrowing down their number to 3 hub miRNAs (hsa-miR-455-3p, hsamiR-548c-3p, and hsa-miR-582-5p) and 9 hub genes (NFIB, DICER1, GSK3B, DCAF7, FGFR1OP, ABHD2, NACC2, NR3C1, and FGF2). Further investigations with different systems biology methods have prioritized NR3C1, ABHD2, and GSK3B as potential genes involved in prostate cancer metastasis owing to their high mutation load and expression status. Interestingly, down regulation of NR3C1 seems to improve the prostate cancer patient survival rate beyond 150 months. The NR3C1, ABHD2, and GSK3B genes are predicted to be targeted by hsa-miR-582-5p, besides some antibodies, PROTACs and inhibitory molecules. Conclusion: This study identified key miRNAs (miR-548c-3p and miR-582-5p) and target genes (NR3C1, ABHD2, and GSK3B) as potential biomarkers for metastatic prostate cancers from large-scale gene expression data using systems biology approaches. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic synovial autoinflammatory disease that destructs the cartilage and bone, leading to disability. The functional regulation of major immunity-related pathways like nuclear factor kappa B (NF-κB), which is involved in the chronic inflammatory reactions underlying the development of RA, remains to be explored. Therefore, this study has adopted statistical and knowledge-based systemic investigations (like gene correlation, semantic similarity, and topological parameters based on graph theory) to study the gene expression status of NF-κB protein family (NKPF) and its regulators in synovial tissues to trace the molecular pathways through which these regulators contribute to RA. A complex protein–protein interaction map (PPIM) of 2,742 genes and 37,032 interactions was constructed from differentially expressed genes (p ≤ 0.05). PPIM was further decomposed into a Regulator Allied Protein Interaction Network (RAPIN) based on the interaction between genes (5 NKPF, 31 seeds, 131 hubs, and 652 bottlenecks). Pathway network analysis has shown the RA-specific disturbances in the functional connectivity between seed genes (RIPK1 , ATG7 , TLR4 , TNFRSF1A , KPNA1 , CFLAR , SNW1 , FOSB , PARVA , CX3CL1 , and TRPC6) and NKPF members (RELA , RELB , NFKB2 , and REL). Interestingly, these genes are known for their involvement in inflammation and immune system (signaling by interleukins, cytokine signaling in immune system, NOD-like receptor signaling, MAPK signaling, Toll-like receptor signaling, and TNF signaling) pathways connected to RA. This study, for the first time, reports that SNW1, along with other NK regulatory genes, plays an important role in RA pathogenesis and might act as potential biomarker for RA. Additionally, these genes might play important roles in RA pathogenesis, as well as facilitate the development of effective targeted therapies. Our integrative data analysis and network-based methods could accelerate the identification of novel drug targets for RA from high-throughput genomic data. [ABSTRACT FROM AUTHOR]