مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
From Genes to Metabolism: The Role of SNPs and Hexokinase in Prostate Cancer Development
From Genes to Metabolism: The Role of SNPs and Hexokinase in Prostate Cancer Development
Daryoush Norouzian,1,*Sanaz Seraj,2Mohammad Mahdi Eslami,3Reza Mirlouhi,4
2. Department of Nanobiotechnology and Biomimetics, School of Life science Engineering, College of Interdisciplinary Science and Technology, University of Tehran, Tehran, 14399-57131, Iran
Introduction: Prostate cancer is a leading malignancy among men worldwide, with both environmental and genetic factors contributing to disease risk. Single nucleotide polymorphisms (SNPs) across multiple genes have been shown to significantly influence susceptibility, progression, and treatment response. In this study, we systematically analyzed SNPs across approximately 100 prostate cancer–related genes and identified over 300 variants of potential relevance. Among these, polymorphisms in PRNCR1, PTEN, BRCA2, and the TMPRSS2:ERG fusion emerged as particularly important based on recent literature. Using bioinformatic tools, we explored the structural and functional implications of these SNPs, while also comparing hexokinase (HK) activity in normal and malignant prostate cells. Our findings highlight the integration of genetic and metabolic alterations in driving prostate cancer biology.Prostate cancer (PCa) remains a major cause of cancer morbidity and mortality. While environmental exposures play a role, inherited genetic susceptibility has been shown to markedly influence disease onset and progression. Genome-wide association studies (GWAS) and sequencing projects over the last decade have identified numerous SNPs in genes involved in androgen receptor regulation, tumor suppression, DNA repair, and metabolic pathways. In our dataset, covering ~100 candidate genes and >300 SNPs, several patterns were observed. Long non-coding RNA PRNCR1 harbors risk-associated SNPs (rs1016343, rs1456315) that modulate androgen receptor signaling. The tumor suppressor PTEN is frequently deleted or mutated in prostate tumors, with SNPs contributing to PI3K/AKT pathway dysregulation and metabolic rewiring. Variants in BRCA2 compromise homologous recombination, leading to genomic instability and aggressive tumor phenotypes. The TMPRSS2:ERG fusion, present in nearly half of PCa cases, reshapes transcriptional programs and interacts with other genomic lesions. Alongside these genetic alterations, hexokinase enzymes—particularly HK2—play distinct roles in normal versus malignant cells. In healthy prostate tissue, HK functions mainly in basal energy metabolism, while in cancer, HK2 supports the Warburg effect and acts as a signaling hub by binding mitochondria to suppress apoptosis. This dual role underscores how genetic drivers and metabolic reprogramming converge in prostate cancer.
Methods: We performed a bioinformatic analysis of prostate cancer–associated SNPs collected from published GWAS and genetic association studies (2021–2025). A total of ~100 genes and more than 300 SNPs were included. SNP annotation and sequence alignment were performed using MEGA software, and population genetics indices were calculated to assess allele frequency and diversity. Functional predictions were cross-referenced with peer-reviewed reports. To highlight key molecular mechanisms, we compared major genes frequently cited in recent literature, including PRNCR1, PTEN, BRCA2, and TMPRSS2. Structural and functional insights into hexokinase were also derived from protein modeling data, comparing normal versus malignant cell states.
Results: Our integrative analysis confirmed that SNPs across a wide range of genes contribute to prostate cancer susceptibility. Among the 300+ SNPs investigated, those in PRNCR1 (e.g., rs1016343) were strongly associated with androgen receptor dysregulation. PTEN variants and loss-of-function mutations correlated with PI3K/AKT activation and altered glucose metabolism. BRCA2 variants (rs144848, rs28897754) were consistently linked with defective DNA repair and aggressive tumor behavior. The TMPRSS2:ERG fusion was detected in nearly 50% of cases, often co-occurring with SNPs in regulatory loci, suggesting cooperative oncogenic effects.Although our dataset spanned many genes—including TP53, EGFR, IL6, VEGFA, and MTHFR—these four drivers emerged as particularly influential in the context of prostate cancer progression. On the metabolic level, HK2 exhibited elevated enzymatic activity and anti-apoptotic signaling properties in malignant cells, contrasting with its limited metabolic role in normal prostate cells. This highlights a convergence of genetic risk factors with metabolic transformation in shaping tumor biology.
Conclusion: By analyzing over 100 genes and 300 SNPs, our study demonstrates that prostate cancer arises from complex interactions between genetic variation and metabolic rewiring. While many loci contribute to susceptibility, polymorphisms in PRNCR1, PTEN, BRCA2, and the TMPRSS2:ERG fusion were identified as particularly critical, consistent with findings in recent literature. Moreover, the dual driving and signaling role of hexokinase underscores the importance of considering metabolic enzymes alongside genetic markers. Our findings suggest that integrating SNP profiling with metabolic pathway analysis may provide a more comprehensive strategy for risk prediction and precision therapy in prostate cancer.