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Published on: August 19, 2021
KCNK9 could be a prognostic biomarker in uterine corpus endometrial carcinoma
Zhang-Lu An1, Yue-Qian Gao1, Zhi-Ming Wang2
1Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Shanghai, China.
Background:
Uterine corpus endometrial carcinoma (UCEC) incidence is rising, necessitating novel prognostic biomarkers. Potassium two pore domain channel subfamily K member 9 (KCNK9) exhibits oncogenic functions in other cancers, but its prognostic and immunological roles in UCEC remain unclear. This study aimed to evaluate the prognostic significance of KCNK9 and its association with the tumor microenvironment (TME) in UCEC.
Methods:
We integrated multi-omics data from The Cancer Genome Atlas (TCGA) UCEC cohort (n=553 tumors, 35 normals). Differential expression, survival (Kaplan-Meier, Cox regression), and immune cell infiltration (CIBERSORT) analyses were performed. Findings were validated using an independent Gene Expression Omnibus (GEO) cohort (GSE17025, n=79 tumors, 12 normals) and immunohistochemistry (IHC) on patient-derived tissues. To explore potential causality and regulatory mechanisms, supplementary two-sample Mendelian randomization (MR), clustered regularly interspaced short palindromic repeats (CRISPR) dependency, and DNA methylation-expression correlation analyses were conducted.
Results:
KCNK9 was significantly overexpressed in UCEC at mRNA and protein levels (P<0.05). High KCNK9 expression correlated with advanced tumor grade and independently predicted reduced overall survival (OS) [adjusted hazard ratio (HR) =1.141, 95% confidence interval (CI): 1.063-1.223, P=0.0002] and progression-free survival (PFS) (adjusted HR =1.140, 95% CI: 1.064-1.222, P=0.0002). An immunosuppressive TME characterized by decreased cytotoxic T-cell infiltration was associated with high KCNK9. MR analysis suggested a potential causal link between genetically predicted KCNK9 expression and UCEC risk [inverse-variance weighted (IVW) odds ratio (OR) =1.0096, P=1.05×10-29].
Conclusions:
KCNK9 is a robust, independent prognostic biomarker linked to an immunosuppressive TME in UCEC. Supported by multi-omics and genetic evidence, KCNK9 is nominated as a high-priority candidate for future mechanistic and therapeutic exploration.
