Interplay Between Type 2 Diabetes Susceptibility and Prostate Cancer Progression: Functional Insights into C2CD4A
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background/Objective: Biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer indicates disease progression. Although type 2 diabetes mellitus (T2D) shows a paradoxical association with prostate cancer risk, the prognostic role of T2D-related genetic variants remains unclear. Methods: We analyzed 113 common T2D susceptibility-related single-nucleotide polymorphisms (SNPs) in 644 Taiwanese men with localized prostate cancer (D’Amico risk classification: 12% low, 34% intermediate, and 54% high) treated with RP. Associations between SNPs and BCR were assessed using Cox regression, adjusting for key clinicopathological factors. Functional annotation was performed using HaploReg and FIVEx, while The Cancer Genome Atlas transcriptomic data were analyzed for C2 calcium-dependent domain-containing 4A (C2CD4A) expression. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore related biological pathways. Results: C2CD4A SNP rs4502156 was independently associated with a reduced risk of BCR (hazard ratio = 0.80, p = 0.035). The protective C allele correlated with higher C2CD4A expression. Low C2CD4A expression is associated with advanced pathological stages, higher Gleason scores, and disease progression. GSEA revealed negative enrichment of mitotic and chromatid segregation pathways in high-C2CD4A-expressing tumors, with E2F targets being the most suppressed. GSVA confirmed an inverse correlation between C2CD4A expression and E2F pathway activity, with CDKN2C as a co-expressed functional gene. Conclusions: The T2D-related variant rs4502156 in C2CD4A independently predicts a lower risk of BCR, potentially via suppression of the E2F pathway, and may serve as a germline biomarker for postoperative risk stratification.
Source: Diagnostics
Institutions: National Yang Ming Chiao Tung University, China Medical University, Mackay Medical University, National Taiwan University, National Taiwan University Hospital, Tajen University, Kaohsiung Veterans General Hospital, National Yang Ming University, E-Da Hospital, I-Shou University, National Sun Yat-sen University, Kaohsiung Medical University, Kaohsiung Medical University Chung-Ho Memorial Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,137
Awards: G1201208807, G1202863552, Develop a Personalized Recommendation System and Accurate Detection Biochips for Evaluating the Therapeutic Efficacy of Second-Generation Hormone Drugs in the Treatment of Prostate Cancer( II ), G1296856295, G2098798637, G2261850885, Develop a Personalized Recommendation System and Accurate Detection Biochips for Evaluating the Therapeutic Efficacy of Second-Generation Hormone Drugs in the Treatment of Prostate Cancer( I ), G3352717642, G3882157870, G4115157685, Establishment of a Human Bio-Database for Second-Generation Hormone Therapy-Resistant Prostate Cancer and Development of an Orthotopic Animal Model with Therapy-Resistant Prostate Cancer for Developing and Validating the Novel Diagnostic and Therapeutic Method( I ), The Interaction among Inter-Individual Genetic Variability, Nutritional Status, and Prostate Cancer Incidence and Mortality, Develop a Personalized Recommendation System and Accurate Detection Biochips for Evaluating the Therapeutic Efficacy of Second-Generation Hormone Drugs in the Treatment of Prostate Cancer( III ), G5486581554, G5553931825, G5691228076, Establishment of a Human Bio-Database for Second-Generation Hormone Therapy-Resistant Prostate Cancer and Development of an Orthotopic Animal Model with Therapy-Resistant Prostate Cancer for Developing and Validating the Novel Diagnostic and Therapeutic Method( II ), The Association between Gene Polymorphisms and Plasma Concentration of Tissue Inhibitors of Metalloproteinase 3, Long Interspersed Nuclear Element-1 Methylation, Plasma Folate and Vitamin B6 and B12 Concentration and Renal Cell Carcinoma, G8164685962, Precision Nutrition: Targeting the Folate-Genome in Prostate Cancer, G897092911
OpenAlex ID: W4415809443