LCAT exhibits subtype specific prognostic and immunometabolic associations in renal cell carcinoma

The three major renal cell carcinoma subtypes-chromophobe renal cell carcinoma (KICH), clear cell renal cell carcinoma (KIRC), and papillary renal cell carcinoma (KIRP)-show marked differences in molecular programs and tumor microenvironmental features, supporting the need for subtype-resolved evaluation of candidate metabolic biomarkers.

Using TCGA-based transcriptomic and clinical data, we evaluated LCAT expression and its associations with overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). We further assessed LCAT copy-number variation (CNV), DNA methylation, DNA methyltransferase correlations, m6A-related regulators, and relationships with the tumor immune microenvironment and functional pathways using established public platforms.

LCAT expression was decreased in KICH but increased in KIRC and KIRP relative to normal kidney tissues. Kaplan-Meier analyses showed that low LCAT was associated with shorter OS/DSS/PFS in KICH, whereas high LCAT was associated with shorter OS/DSS/PFS in KIRC; in KIRP, higher LCAT was associated with improved DSS but not OS/PFS. Immune analyses revealed subtype-specific changes in ESTIMATE-derived scores, immune-cell enrichment, and immune-related signatures, with significantly lower StromalScore and ESTIMATEScore in the LCAT-high group in KIRP and altered immune-cell subsets across all three subtypes. LCAT correlated with multiple immunomodulators and MHC molecules. LCAT expression was not correlated with tumor mutational burden (TMB) in any subtype, and MSI showed a significant positive association with LCAT only in KICH. CNV analyses demonstrated a positive CNV-mRNA correlation (most pronounced in KIRP); CNV deletions were consistently associated with the poorest survival in KICH and KIRP, whereas CNV status was not prognostically significant in KIRC. DNA methylation was inversely associated with LCAT expression in KIRC, and higher methylation predicted worse OS only in KICH. LCAT expression was positively correlated with multiple m6A regulators in KIRC and KIRP but not in KICH.

LCAT displays subtype-dependent prognostic and immunometabolic associations in RCC and may serve as a candidate biomarker for stratification; further external-cohort and experimental validation is warranted.