Abstract / Summary
Background and Objectives: LHFPL5 encodes a four-pass transmembrane protein essential for cochlear mechanotransduction, but its molecular behavior in cancer remains poorly defined. We characterized the genomic, epigenetic, transcriptomic, immune, and cellular context of LHFPL5 in clear cell renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD), along with its associations with clinical outcomes. Methods: Retrospective analyses integrated TCGA RNA sequencing, clinical, DNA methylation, copy number, tumor purity, and immune deconvolution data. Transcriptome-wide associations and Hallmark enrichment defined LHFPL5-associated programs. Continuous-expression Cox models estimated hazard ratios (HRs) per standard-deviation increase, adjusted for age, sex, and pathological stage. GEO cohorts assessed external reproducibility, matched TCGA expression pipelines assessed processing sensitivity, and three non-TCGA single-cell datasets examined cellular localization. Results: LHFPL5 showed distinct molecular contexts in KIRC and LUAD. In KIRC, higher expression remained associated with poorer overall survival after clinical adjustment (528 patients; 174 deaths; HR = 1.36, 95% CI 1.21–1.53; p = 2.42 × 10−7), while subtype and immune fractions showed limited statistical overlap with the association. In LUAD, expression covaried with copy-number state and showed a weak inverse relationship with first-exon methylation. Proliferation-related transcriptional programs were associated with survival, although enrichment support depended on the multiple-testing procedure. The primary STAR-derived LUAD analysis was null (485 patients; 177 deaths; HR = 1.02, 95% CI 0.89–1.18; p = 0.770), and survival inference varied with RNA processing. External adjusted replication was inconclusive. Single-cell detection was sparse in KIRC and one LUAD dataset; another LUAD cohort showed more frequent epithelial detection without resolved malignant-cell identity. Conclusions: LHFPL5 exhibits cancer-specific molecular architecture. LUAD showed copy-number, methylation, and proliferation-related associations, whereas KIRC showed a distinct molecular context with an independent survival signal. These findings support context-dependent LHFPL5 regulation and prioritize genomic, epigenetic, and transcriptional mechanisms for functional investigation.