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A five-gene signature is a prognostic biomarker in pan-cancer and related with immunologically associated extracellular matrix.

ABSTRACT: The tumor microenvironment (TME) is related to extracellular matrix (ECM) dynamics and has a broad fundamental and mechanistic role in tumorigenesis and cancer progression. We hypothesized that ECM regulators might play an essential role in pan-cancer attribution by causing a generic effect through its regulation of the dynamics of ECM alteration. By analyzing data from TCGA using GSEA and univariate Cox regression analysis, we found that ECM regulator genes were significantly enriched and contributed to mortality in various cancer types. Notably, UMAP analysis revealed that ECM regulator genes dominated the differences between tumor and adjacent normal tissues based on 59 or 31 pan-survival-related ECM gene sets. Subsequently, a five-gene signature consisting of the predominant ECM regulators ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 was identified. We found that this five-gene signature was pro-mortality in 18 types of cancer in TCGA, and validated eleven other cancer types in TCGA and seven types in the TARGET and CoMMpass databases using overall survival analysis. KEGG pathway enrichment and Pearson correlation analysis indicated that these five component genes that were correlated with specific ECM proteins involved in tumorigenesis from the ECM receptor interaction gene set. Additionally, the fitted results of a linear model were applied to strengthen the discovery, demonstrating that the five genes were correlated with immune infiltration score and especially associated with typically immunologically "cold" tumors. We thus conclude that the ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 signature showed a close association with a pan-cancer effect on prognosis and is related to ECM proteins in the TME which corresponding with immunologically "cold" cancer types.

SUBMITTER: Yu C

PROVIDER: S-EPMC8267129 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:One important aim of precision oncology is a personalized treatment of patients. This can be achieved by various biomarkers, especially imaging parameters and gene expression signatures are commonly used. So far, combination approaches are sparse. The aim of the study was to independently validate the prognostic value of the novel positron emission tomography (PET) parameter tumor asphericity (ASP) in non small cell lung cancer (NSCLC) patients and to investigate associations between published gene expression profiles and ASP. This was a retrospective evaluation of PET imaging and gene expression data from three public databases and two institutional datasets. The whole cohort comprised 253 NSCLC patients, all treated with curative intent surgery. Clinical parameters, standard PET parameters and ASP were evaluated in all patients. Additional gene expression data were available for 120 patients. Univariate Cox regression and Kaplan-Meier analysis was performed for the primary endpoint progression-free survival (PFS) and additional endpoints. Furthermore, multivariate cox regression testing was performed including clinically significant parameters, ASP, and the extracellular matrix-related prognostic gene signature (EPPI). In the whole cohort, a significant association with PFS was observed for ASP (p < 0.001) and EPPI (p = 0.012). Upon multivariate testing, EPPI remained significantly associated with PFS (p = 0.018) in the subgroup of patients with additional gene expression data, while ASP was significantly associated with PFS in the whole cohort (p = 0.012). In stage II patients, ASP was significantly associated with PFS (p = 0.009), and a previously published cutoff value for ASP (19.5%) was successfully validated (p = 0.008). In patients with additional gene expression data, EPPI showed a significant association with PFS, too (p = 0.033). The exploratory combination of ASP and EPPI showed that the combinatory approach has potential to further improve patient stratification compared to the use of only one parameter. We report the first successful validation of EPPI and ASP in stage II NSCLC patients. The combination of both parameters seems to be a very promising approach for improvement of risk stratification in a group of patients with urgent need for a more personalized treatment approach.

Project description:Background: The polypyrimidine tract-binding protein (PTBP) nuclear ribonucleoprotein family of proteins, including PTBP1, PTBP2 and PTBP3, regulate the process of cell proliferation, differentiation, apoptosis and carcinogenesis. PTBPs exhibit oncogenic effects in certain tumors. However, the role of PTBPs in pan-cancer remains unclear. Our study examined the clinical significance and mechanism of PTBPs in pan-cancer. Methods: We compared the expression of PTBPs in paired and unpaired tissue samples from the Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression, Kaplan–Meier curves, and time-dependent receiver operating characteristic (ROC) curves were used to assess the prognostic significance of PTBPs in pan-cancer. The cBioPortal database also identified genomic abnormalities in PTBPs. TISIDB, TCGA, and Cellminer were used to investigate the relationship between PTBP expression and immune subtypes, immune checkpoint (ICP) genes, tumor mutational burden (TMB), microsatellite instability (MSI), tumor-infiltrating immune cells, and chemosensitivity. cBioPortal was used to search for PTBP co-expressing genes in pan-cancer, and GO and KEGG enrichment analyses were performed to search for PTBP-related signaling pathways. Results:PTBPs were shown to be widely upregulated in human tumor tissues. PTBP1 showed good prognostic value in ACC, KIRP, and LGG; PTBP2 in ACC and KICH; and PTBP3 in ACC, LGG, and PAAD, with AUC >0.7. PTBPs were differentially expressed in tumor immune subtypes and had a strong correlation with tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME). In addition, PTBP expressions were related to ICP, TMB, and MSI, suggesting that these three PTBPs may be potential tumor immunotherapeutic targets and predict the efficacy of immunotherapy. Enrichment analysis of co-expressed genes of PTBPs showed that they may be involved in alternative splicing, cell cycle, cellular senescence, and protein modification. Conclusion: PTBPs are involved in the malignant progression of tumors. PTBP1, PTBP2 and PTBP3 may be potential biomarkers for prognosis and immunotherapy in pan-cancer and may be novel immunotherapeutic targets.

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A five-gene signature is a prognostic biomarker in pan-cancer and related with immunologically associated extracellular matrix.

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