Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Wen F
PROVIDER: S-EPMC8631969 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor mutation burden (TMB) has been associated with prognosis in various malignancies, but it has yet to be elucidated in hepatocellular carcinoma (HCC). We aimed to investigate the prognostic effects of TMB and its relationship with immune infiltration through multiple databases and whole-exome sequencing, so as to establish a panel model capable of predicting prognosis. The results demonstrated that the prognosis of high TMB group was worse than that of low TMB group, with a cutoff TMB value of 4.9. Enrichment analysis demonstrated that differentially expressed genes were mainly related to T cell activation, cell membrane localization and matrix composition. Tumor immune infiltration analysis revealed the infiltrations of Th2, Th17, and Tgd were up-regulated in high TMB group, while those of Tr1, MAIT, and DC were up-regulated in low TMB group. TMB-Infiltration model fit well with the actual survival observation, with a C-index 0.785 (0.700-0.870), which verified in ICGC-LIRI-JP was 0.650 (0.553-0.747). Additionally, these screened immune genes performed well in predicting tumor vascular invasion with a C-index of 0.847 (0.778-0.916). Overall, these results indicated that patients with high mutation frequency of immune-related genes and high TMB were prone to have worse prognosis and relapse after radical treatment.
| S-EPMC8034943 | biostudies-literature
Project description:Growing evidence highlighted the tumor mutational burden (TMB) as an important feature of carcinogenesis and therapeutic efficacy in esophageal cancer (EC). Our study aimed to explore the genomic landscape and the correlation between TMB and immune cell infiltration in EC patients with or without radiotherapy. The EC patients were categorized into high TMB (TMB-H) and low TMB (TMB-L) groups by the ESTIMATE algorithm, and subgroup analysis was performed based on receiving radiotherapy or not. Univariate regression analysis indicated TMB and TNM stages as high-risk prognostic factors (Hazard ratio > 1 and P < 0.05). Multivariate regression analysis suggested TMB as an independent prognostic factor (Hazard ratio = 1.051, P = 0.003). Kaplan-Meier analysis showed no significant difference of the overall survival (OS) between TMB-H and TMB-L groups (P = 0.082). However, EC patients without radiotherapy in the TMB-H group had significantly decreased OS (P = 0.038) and increased Tregs cell infiltration (P = 0.033). These results suggested TMB as a prognostic marker for EC patients. Especially for patients who did not receive radiotherapy, the prognosis of TMB-H patients was significantly poorer than that of TMB-L patients, which might result from the different regulatory T cell infiltration.
| S-EPMC7093160 | biostudies-literature
Project description:BackgroundOral cavity is the most prevalent site of head and neck squamous cell carcinomas (HNSCCs). Most often diagnosed at a locally advanced stage, treatment is multimodal with surgery as the cornerstone. The aim of this study was to explore the molecular landscape of a homogenous cohort of oral cavity squamous cell carcinomas (OCSCCs), and to assess the prognostic value of tumor mutational burden (TMB), along with classical molecular and clinical parameters.Patients and methodsOne hundred and fifty-one consecutive patients with OCSCC treated with upfront surgery at the Institut Curie were analyzed. Sequencing of tumor DNA from frozen specimens was carried out using an in-house targeted next-generation sequencing panel (571 genes). The impact of molecular alterations and TMB on disease-free survival (DFS) and overall survival (OS) was evaluated in univariate and multivariate analyses.ResultsPathological tumor stage, extranodal spread, vascular emboli, and perineural invasion were associated with both DFS and OS. TP53 was the most mutated gene (71%). Other frequent molecular alterations included the TERT promoter (50%), CDKN2A (25%), FAT1 (17%), PIK3CA (14%), and NOTCH1 (15%) genes. Transforming growth factor-β pathway alterations (4%) were associated with poor OS (P = 0.01) and DFS (P = 0.02) in univariate and multivariate analyses. High TMB was associated with prolonged OS (P = 0.01 and P = 0.02, in the highest 10% and 20% TMB values, respectively), but not with DFS. Correlation of TMB with OS remained significant in multivariate analysis (P = 0.01 and P = 0.005 in the highest 10% and 20% TMB values, respectively). Pathological tumor stage combined with high TMB was associated with good prognosis.ConclusionOur results suggest that a high TMB is associated with a favorable prognosis in patients with OCSCC treated with upfront surgery.
| S-EPMC8207209 | biostudies-literature
Project description:IntroductionTo depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates.MethodsWhole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database.ResultsThe median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P =?0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P <?0.001, P =?0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors.ConclusionThe combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.
| S-EPMC6625041 | biostudies-literature
Project description:In order to explore the prognosis of tumor mutation burden (TMB) and the relationship with tumor infiltrating immune cells in hepatocellular carcinoma (HCC), we downloaded somatic mutation data and transcriptome profiles of 376 HCC patients from The Cancer Genome Atlas (TCGA) cohort. We divided the samples into high-TMB and low-TMB groups. A higher TMB level indicated improved overall survival (OS) and was associated with early pathological stages. One hundred and nine differentially expressed genes (DEGs) were identified in HCC. Moreover, based on four hub TMB-related signatures, we constructed a TMB Prognostic model (TMBPM) that possessed good predictive value with area under curve (AUC) of 0.701. HCC patients with higher TMBPM scores showed worse OS outcomes (p < 0.0001). Moreover, DCs subsets not only revealed higher infiltrating abundance in the high-TMB group, but also correlated with worse OS and hazard risk for high-TMB patients in HCC. Meanwhile, CD8+ T cells and B cells were associated with improved survival outcomes. In sum, high TMB indicates good prognosis for HCC and promotes HCC immune infiltration. Hence, DCs and the four hub TMB-related signatures can be used for predicting the prognosis in HCC as supplements to TMB.
| S-EPMC8109113 | biostudies-literature
Project description:Background:Prostate cancer (PCa) is one of the most common cancers and the fifth leading cause of cancer-related death in men. Immune responses in the tumor microenvironment are hypothesized to be related to the prognosis of PCa patients; however, no studies are available to confirm the same. In this study, we aimed to explore the potential link between these two factors and identify new biomarkers to estimate the survival rate of PCa patients. Methods:A total of 490 cases were obtained from The Cancer Genome Atlas (TCGA) database. The gene expression data were analyzed by the ESTIMATE algorithm to evaluate the immune and stromal scores. The survival rate was calculated according to the case-specific clinical data. Enrichment analysis was performed to discover the main biological processes and signaling pathways of immune responses. We further identified and analyzed hub genes in the protein-protein interaction (PPI) network and evaluated their prognostic values. Results:Immune score significantly correlated with immune cell infiltration and overall survival of PCa patients. The genes CXCR4 and GPR183, identified as hub genes in the PPI network, correlated with immune cell infiltration and prognosis of PCa patients. Conclusion:CXCR4 and GPR183 participate in immune cell infiltration and function in PCa patients. The immune score, as well as the expression of CXCR4 and GPR183 in prostate cancer tissues, could be potential indexes for the prognosis of prostate cancer.
| S-EPMC7662134 | biostudies-literature
Project description:The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n?=?213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p?=?0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p?<?0.01 and HR 2.8, p?=?0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p?=?0.03). In the HPV- cohort (n?=?158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p?<?0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.
| S-EPMC6004546 | biostudies-literature
Project description:BackgroundLung squamous cell carcinoma (LUSC) is a highly malignant tumor with an extremely poor prognosis. Immune checkpoint inhibitors (ICIs) improve survival in some patients with LUSC. Tumor mutation burden (TMB) is a useful biomarker to predict the efficacy of ICIs. However, predictive and prognostic factors related to TMB in LUSC remain elusive. This study aimed to find effective biomarkers based on TMB and immune response and establish a prognostic model of LUSC.MethodsWe downloaded Mutation Annotation Format (MAF) files from The Cancer Genome Atlas (TCGA) database and identified immune-related differentially expressed genes (DEGs) between high- and low-TMB groups. The prognostic model was established using cox regression. The primary outcome was overall survival (OS). Receiver operating characteristic (ROC) curves and calibration curves were used to verify the accuracy of the model. GSE37745 acted as external validation set. The expression and prognosis of hub genes as well as their correlation with immune cells and somatic copy number variation (sCNA) were analyzed.ResultsThe TMB of patients with LUSC was correlated with prognosis and stage. High TMB group had higher survival rate (P<0.001). Five TMB-related hub immune genes (TINAGL1, FGFR2, CTSE, SFTPA1, and IGHV7-81) were identified and the prognostic model was constructed. The survival time of high-risk group was significantly shorter than that of low-risk group (P<0.001). The validation results of the model were quite stable in different data sets, and the area under curve (AUC) of training set and validation set were 0.658 and 0.644, respectively. Calibration chart, risk curve, and nomogram revealed that the prognostic model was reliable in predicting the prognostic risk of LUSC, and the risk score of the model could be used as an independent prognostic factor for LUSC patients (P<0.001).ConclusionsOur results show that high TMB is associated with poor prognosis in patients with LUSC. The prognostic model related to TMB and immunity can effectively predict the prognosis of LUSC, and risk score is one of the independent prognostic factors of LUSC. However, this study still has some limitations, which need to be further verified in large-scale and prospective studies.
| S-EPMC10089836 | biostudies-literature
Project description:Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p=0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p<0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46-3.65; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), disease-specific survival (HR 2.23, 95% CI 1.41-3.53; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05-2.53; p=0.029; and HR 0.98, 95% CI 0.96-1.00; p=0.063) in multivariate models. PATIENT SUMMARY: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden.
| S-EPMC5809230 | biostudies-literature
Project description:Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.
| S-EPMC8902256 | biostudies-literature