Pathology, research and practice · 2026
A seven-gene signature associated with inner mitochondrial membrane protein-defined molecular subtypes for prognostic stratification in gastric cancer.
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Yang Guangming, Ma Ting, Yao Li, Li Zeshan, Yuan Lizhen, Wan Deli
Аннотация
BACKGROUND: Inner membrane mitochondrial proteins (IMMPs) are involved in biological events relevant to tumor development. However, how IMMP-related genes (IMMT-RGs) contribute to prognosis and function in gastric cancer (GC) has not been fully characterized. This work sought to screen prognostically informative IMMT-RGs in GC and to delineate their possible molecular associations.
METHODS: We analyzed transcriptomic profiles and clinical annotations from TCGA-GC and GSE84426. In TCGA-GC, differentially expressed genes 1 (DEGs1) were obtained by comparing GC tissues with control samples. Prognosis-related IMMT-RGs identified by univariate Cox analysis were used to stratify GC cases into two molecular subtypes, after which subtype-related DEGs2 were determined. The overlap of DEGs1 and DEGs2 was carried forward. Prognostic candidates were refined through univariate Cox regression, PH assessment, and LASSO regression. A risk score was calculated from the expression of the selected genes and their coefficients. Univariate and multivariate Cox analyses of clinicopathologic factors were applied to define independent prognostic variables. Drug sensitivity was investigated using the GDSC resource.
RESULTS: The DEGs1-DEGs2 intersection yielded 802 genes for additional evaluation. RIMS1, IGFN1, ALLC, GRIA3, KLK5, LMX1A, and SLITRK4 were finally included as prognostic genes. Based on this seven-gene panel, a risk score was constructed, and ROC curves were used to assess 1-, 3-, and 5-year survival prediction in GC. Calibration curves showed a certain degree of agreement between the nomogram predictions incorporating independent prognostic factors and the observed outcomes. Drug sensitivity analysis showed that, after Benjamini-Hochberg correction, 56 drugs showed significant differences in predicted IC50 values between the two risk groups (adj. P < 0.05); among them, CCT007093, VX-702, and AP24534 showed the largest differences in predicted IC50 between the groups and were therefore selected as representative candidate drugs for focused presentation.
CONCLUSION: These seven IMMP-related genes (RIMS1, IGFN1, ALLC, GRIA3, KLK5, LMX1A, and SLITRK4) may represent candidate prognostic biomarkers and provide exploratory clues for further investigation of related molecular processes in gastric cancer.
METHODS: We analyzed transcriptomic profiles and clinical annotations from TCGA-GC and GSE84426. In TCGA-GC, differentially expressed genes 1 (DEGs1) were obtained by comparing GC tissues with control samples. Prognosis-related IMMT-RGs identified by univariate Cox analysis were used to stratify GC cases into two molecular subtypes, after which subtype-related DEGs2 were determined. The overlap of DEGs1 and DEGs2 was carried forward. Prognostic candidates were refined through univariate Cox regression, PH assessment, and LASSO regression. A risk score was calculated from the expression of the selected genes and their coefficients. Univariate and multivariate Cox analyses of clinicopathologic factors were applied to define independent prognostic variables. Drug sensitivity was investigated using the GDSC resource.
RESULTS: The DEGs1-DEGs2 intersection yielded 802 genes for additional evaluation. RIMS1, IGFN1, ALLC, GRIA3, KLK5, LMX1A, and SLITRK4 were finally included as prognostic genes. Based on this seven-gene panel, a risk score was constructed, and ROC curves were used to assess 1-, 3-, and 5-year survival prediction in GC. Calibration curves showed a certain degree of agreement between the nomogram predictions incorporating independent prognostic factors and the observed outcomes. Drug sensitivity analysis showed that, after Benjamini-Hochberg correction, 56 drugs showed significant differences in predicted IC50 values between the two risk groups (adj. P < 0.05); among them, CCT007093, VX-702, and AP24534 showed the largest differences in predicted IC50 between the groups and were therefore selected as representative candidate drugs for focused presentation.
CONCLUSION: These seven IMMP-related genes (RIMS1, IGFN1, ALLC, GRIA3, KLK5, LMX1A, and SLITRK4) may represent candidate prognostic biomarkers and provide exploratory clues for further investigation of related molecular processes in gastric cancer.