مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Meta-Analysis and Bioinformatic Insights into Functional Impacts of Signaling and Carbohydrate Metabolism Gene SNPs in Skin Cancer
Meta-Analysis and Bioinformatic Insights into Functional Impacts of Signaling and Carbohydrate Metabolism Gene SNPs in Skin Cancer
Dr. Darioush Noruzian,1,*Farnaz Ghayour Babaei,2Dr. Mohammad Mahdi Eslami,3Dr. Reza Mirlohi,4
2. Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran 3. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran 4. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran
Introduction: Cutaneous malignancies result from intricate molecular interactions, yet the precise hierarchy of genetic events remains unclear. Prior studies on high impact Single Nucleotide Polymorphisms (SNPs) in oncogenic signaling genes (BRAF, NRAS, KIT, PTCH1, FAT1, NOTCH1) and carbohydrate metabolism enzymes (HK2, PKM2, LDHA, G6PD, FBP1) indicate that signaling pathway alterations often serve as cancer‑initiating events. In contrast, metabolic gene variants more frequently contribute to tumor maintenance and progression, including metabolic reprogramming characteristic of the Warburg effect. Despite FBP1’s established role in epidermal homeostasis and tumor suppression in various cancers, its direct function in skin cancer remains largely uninvestigated a gap that warrants attention.
Methods: We identified high citation SNPs from scientific databases and peer‑reviewed literature. Sequence alignments and functional annotations were performed using MEGA Gene software. For each variant, potential effects on the Michaelis constant (Km), enzyme structural stability, and loss of function probability were inferred based on variant type (missense, stop‑gained, synonymous) and mapped to catalytic or regulatory sites using literature data and protein domain resources.
Results: In metabolic genes, benign or uncertain significance missense substitutions located near substrate‑binding or catalytic residues were predicted to reduce Km enhancing substrate affinity or to subtly alter conformations favoring glycolysis under hypoxia. Stop‑gained variants were rare, suggesting limited direct enzymatic loss; however, several missense changes appeared to sustain flux through glucose phosphorylation (HK2), pyruvate‑to‑lactate conversion (LDHA), and NADPH production (G6PD). In signaling genes, pathogenic missense or stop‑gained SNPs in BRAF, NRAS, PTCH1, and NOTCH1 were linked to constitutive pathway activation, indirectly amplifying metabolic enzyme activity. While FBP1 expression was downregulated in skin cancer datasets, no dedicated study has directly examined its oncological role.
Conclusion: Our integrated analysis supports a functional division of labor: signaling gene SNPs act as oncogenic initiators via constitutive pathway activation, whereas metabolic‑gene variants fine‑tune catalytic dynamics (e.g., Km reduction) to reinforce the Warburg phenotype. The predominance of signaling mutations as initial drivers highlights the value of reprioritizing therapeutic targets toward early pathway disruption, while late‑stage interventions may focus on metabolic sustainers including underexplored candidates such as FBP1 requiring further in context validation.