Interplay Between Type 2 Diabetes Susceptibility and Prostate Cancer Progression: Functional Insights into C2CD4A.

Area of Science:

• Genetics and Genomics
• Oncology
• Endocrinology

Background:

• Biochemical recurrence (BCR) after prostate cancer surgery signals disease progression.
• The link between type 2 diabetes mellitus (T2D) and prostate cancer risk is complex, and the prognostic impact of T2D-related genetic factors is not well understood.

Purpose of the Study:

• To investigate the association between T2D susceptibility single-nucleotide polymorphisms (SNPs) and BCR risk in men undergoing radical prostatectomy (RP).
• To explore the functional role of identified SNPs in prostate cancer progression and recurrence.

Main Methods:

• Analysis of 113 T2D-related SNPs in 644 Taiwanese prostate cancer patients treated with RP.
• Cox regression models were used to assess SNP associations with BCR, adjusting for clinical factors.
• Functional analyses included gene expression (C2 calcium-dependent domain-containing 4A - C2CD4A), pathway analysis (GSEA, GSVA), and correlation with clinicopathological features.

Main Results:

• The T2D-related SNP rs4502156 in C2CD4A was independently associated with a reduced risk of BCR (HR=0.80, p=0.035).
• The protective allele correlated with higher C2CD4A expression, which was linked to less advanced disease.
• High C2CD4A expression was associated with suppressed E2F pathway activity, suggesting a mechanism for reduced tumor progression.

Conclusions:

• The T2D-related C2CD4A variant rs4502156 serves as an independent predictor of lower BCR risk post-prostatectomy.
• This variant may exert its protective effect by suppressing the E2F pathway, impacting cell proliferation.
• The rs4502156 SNP could be a valuable germline biomarker for stratifying postoperative risk in prostate cancer patients.