A Novel Clinical Six-Flavoprotein-Gene Signature Predicts Prognosis in Esophageal Squamous Cell Carcinoma

Flavoproteins and their interacting proteins play important roles in mitochondrial electron transport, fatty acid degradation, and redox regulation. However, their clinical significance and function in esophageal squamous cell carcinoma (ESCC) are little known. Here, using survival analysis and machine learning, we mined 179 patient expression profiles with ESCC in GSE53625 from the Gene Expression Omnibus (GEO) database and constructed a signature consisting of two flavoprotein genes (GPD2 and PYROXD2) and four flavoprotein interacting protein genes (CTTN, GGH, SRC, and SYNJ2BP). Kaplan–Meier analysis revealed the signature was significantly associated with the survival of ESCC patients (mean survival time: 26.77 months in the high-risk group vs. 54.97 months in the low-risk group, P<0.001, n = 179), and time-dependent ROC analysis demonstrated that the six-gene signature had good predictive ability for six-year survival for ESCC (AUC = 0.86, 95% CI: 0.81–0.90). We then validated its prediction performance in an independent set by RT-PCR (mean survival: 15.73 months in the high-risk group vs. 21.1 months in the low-risk group, P=0.032, n = 121). Furthermore, RNAi-mediated knockdown of genes in the flavoprotein signature led to decreased proliferation and migration of ESCC cells. Taken together, CTTN, GGH, GPD2, PYROXD2, SRC, and SYNJ2BP have an important clinical significance for prognosis of ESCC patients, suggesting they are efficient prognostic markers and potential targets for ESCC therapy.

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A Four-gene Autophagy-related Prognostic Signature and Its Association With Immune Landscape in Lung Squamous Cell Carcinoma

10.21203/rs.3.rs-125355/v1 ◽

2020 ◽

Author(s):

Lumeng Luo ◽

Minghe Lv ◽

Xuan Li ◽

Tiankui Qiao ◽

Kuaile Zhao ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Risk Score ◽

Squamous Cell ◽

Immune Suppression ◽

Risk Group ◽

Lung Squamous Cell Carcinoma ◽

High Risk Group ◽

Low Risk

Abstract Background: Recent advances in immune checkpoint inhibitors (ICIs) have dramatically changed the therapeutic strategy against lung squamous cell carcinoma (LUSC). In the era of immunotherapy, effective biomarkers to better predict outcomes and inform treatment decisions for patients diagnosed with LUSC are urgently needed. We hypothesized that immune contexture of LUSC is potentially dictated by tumor intrinsic events, such as autophagy. Thus, we attempted to construct an autophagy-related risk signature and examine its prediction value for immune phenotype in LUSC.Method: The expression profile of LUSC was obtained from the cancer genome atlas (TCGA) database and the profile of autophagy-related genes (ARGs) was extracted. The survival‑related ARGs (sARGs) was screened out through survival analyses. Random forest was performed to select the sARGs and construct a prognostic risk signature based on these sARGs. The signature was further validated by receiver operating characteristic (ROC) analysis and Cox regression. GEO dataset was used as an independent testing dataset. Patients were divided into high-risk and low-risk group based on the risk score. Then, gene set enrichment analysis (GSEA) was conducted between the two groups. The Single-Sample GSEA (ssGSEA) was introduced to quantify the relative infiltration of immune cells. The correlations between risk score and several main immune checkpoints were examined. And the ESTIMATE algorithm was used to calculate the estimate/immune/stromal scores of the LUSC. Results: Four ARGs (CFLAR, RGS19, PINK1 and CTSD) with the most significant prognostic values were enrolled to construct the risk signature. Patients in high-risk group had better prognosis than the low-risk group (P < 0.0001 in TCGA; P < 0.01 in GEO) and considered as an independent prognosis factor. We also found that high-risk group indicated an immune-suppression status and had higher levels of infiltrating regulatory T cells and macrophages, which are correlated with worse outcome. Besides, risk score showed a significantly positive correlation with the expression of PD-1 and CTLA4, as well as estimate score and immune score.Conclusion: This study established a novel autophagy-related four-gene prognostic risk signature, and the autophagy-related scores are associated with immune landscape of LUSC, with higher score indicating a stronger immune-suppression status.

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Ferroptosis-related gene signature predicts the prognosis in Oral squamous cell carcinoma patients

BMC Cancer ◽

10.1186/s12885-021-08478-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hongyu Li ◽

Xiliu Zhang ◽

Chen Yi ◽

Yi He ◽

Xun Chen ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Immune Status ◽

Risk Group ◽

Risk Groups ◽

Gene Signature ◽

High Risk Group

Abstract Background The prognosis of oral squamous cell carcinoma (OSCC) patients is difficult to predict or describe due to its high-level heterogeneity and complex aetiologic factors. Ferroptosis is a novel form of iron-dependent cell death that is closely related to tumour growth and progression. This study aims to clarify the predictive value of ferroptosis-related genes (FRGs) on the overall survival(OS) of OSCC patients. Methods The mRNA expression profile of FRGs and clinical information of patients with OSCC were collected from the TCGA database. Candidate differentially expressed ferroptosis-related genes (DE-FRGs) were identified by analysing differences between OSCC and adjacent normal tissues. A gene signature of prognosis-related DE-FRGs was established by univariate Cox analysis and LASSO analysis in the training set. Patients were then divided into high- and low-risk groups according to the cut-off value of risk scores, A nomogram was constructed to quantify the contributions of gene signature and clinical parameters to OS. Then several bioinformatics analyses were used to verify the reliability and accuracy of the model in the validation set. Finally, single-sample gene set enrichment analysis (ssGSEA) was also performed to reveal the underlying differences in immune status between different risk groups. Results A prognostic model was constructed based on 10 ferroptosis-related genes. Patients in high-risk group had a significantly worse OS (p < 0.001). The gene signature was verified as an independent predictor for the OS of OSCC patients (HR > 1, p < 0.001). The receiver operating characteristic curve displayed the favour predictive performance of the risk model. The prediction nomogram successfully quantified each indicator’s contribution to survival and the concordance index and calibration plots showed its superior predictive capacity. Finally, ssGSEA preliminarily indicated that the poor prognosis in the high-risk group might result from the dysregulation of immune status. Conclusion This study established a 10-ferroptosis-releated gene signature and nomogram that can be used to predict the prognosis of OSCC patients, which provides new insight for future anticancer therapies based on potential FRG targets.

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Identification and Validation of a Hypoxia-Immune-Based Prognostic mRNA Signature for Oral Squamous Cell Carcinoma

10.21203/rs.3.rs-596220/v1 ◽

2021 ◽

Author(s):

Shaohua Lv ◽

Jianhao Li ◽

Songlin Piao ◽

jichen Li

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Immune Status ◽

Cox Regression ◽

Risk Group ◽

Gene Signature ◽

Low Risk

Abstract Background: Oral squamous cell carcinoma (OSCC) is a frequently encountered head and neck malignancy. Increasing evidence points towards an aberrant immune response and chronic cell hypoxia in the development of OSCC. However, there is a lack of a reliable hypoxia-immune-based gene signature that may serve to accurately prognosticate OSCC. Methods: The mRNA expression data of OSCC patients was extracted from the TCGA database. Hypoxia status was identified using the t-distributed Stochastic Neighbor Embedding (t-SNE) algorithm. Both ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) was used for further evaluation of immune status. The DEGs in different hypoxia and immune status were determined. A Machine learning method-Least Absolute Shrinkage and Selection operator (LASSO) Cox regression analysis allowed us to select prognostically significant hypoxia- and immune-related mRNAs in order to construct prognostic gene signature to predict the overall survival (OS) of OSCC patients. Results: A total of 773 DEGs were classified into either Hypoxia_High and Hypoxia_Low groups. Immune-associated DEG expressions were used to divide individuals into Immune_High, Immune_ Medium and Immune_Low groups. A total of 193 mRNAs which were significant in both immune function and hypoxia status were identified. With the Lasso Cox regression model, 8 signature mRNAs (FAM122C, RNF157, RANBP17, SOWAHA, KIAA1211, RIPPLY2, INSL3, and DNAH1) associated with OS were selected for further calculation of their respective risk scores. The risk score showed a significant association with age, perineural and lymphovascular invasion. In the GEO validation cohort, a better OS was observed in patients from the low-risk group in comparison to those in the high-risk group. High-risk patients also demonstrated different immune infiltration characteristics from the low-risk group. All individuals from the TCGA OSCC cohort showed similar trends in all 6 immune checkpoints, with those of the low-risk group yielding higher immune indicator scores in contrast to their high-risk counterparts. Conclusion: The hypoxia-immune-based gene signature has prognostic potential in OSCC.

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Identification of a novel CpG methylation signature to predict prognosis in lung squamous cell carcinoma

Cancer Biomarkers ◽

10.3233/cbm-201564 ◽

2020 ◽

pp. 1-11

Author(s):

Nan Lee ◽

Xuelian Xia ◽

Hui Meng ◽

Weiliang Zhu ◽

Xiankai Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

High Risk ◽

Cell Carcinoma ◽

Squamous Cell ◽

Risk Group ◽

Lung Squamous Cell Carcinoma ◽

High Risk Group ◽

Low Risk ◽

Risk Patients

BACKGROUND: DNA methylation plays a vital role in modulating genomic function and warrants evaluation as a biomarker for the diagnosis and treatment of lung squamous cell carcinoma (LUSC). OBJECTIVE: In this study, we aimed to identify effective potential biomarkers for predicting prognosis and drug sensitivity in LUSC. METHODS: A univariate Cox proportional hazards regression analysis, a random survival forests-variable hunting (RSFVH) algorithm, and a multivariate Cox regression analysis were adopted to analyze the methylation profile of patients with LUSC included in public databases: The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO). RESULTS: A methylated region consisting of 3 sites (cg06675147, cg07064331, cg20429172) was selected. Patients were divided into a high-risk group and a low-risk group in the training dataset. High-risk patients had shorter overall survival (OS) (hazard ratio [HR]: 2.72, 95% confidence interval [CI]: 1.82–4.07, P< 0.001) compared with low-risk patients. The accuracy of the prognostic signature was validated in the test and validation cohorts (TCGA, n= 94; GSE56044, n= 23). Gene set variation analysis (GSVA) showed that activity in the cell cycle/mitotic, ERBB, and ERK/MAPK pathways was higher in the high-risk compared with the low-risk group, which may lead to differences in OS.Interestingly, we observed that patients in the high-risk group were more sensitive to gemcitabine and docetaxel than the low-risk group, which is consistent with results of the GSVA. CONCLUSION: We report novel methylation sites that could be used as powerful tools for predicting risk factors for poorer survival in patients with LUSC.

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A Ferroptosis-Related Long Non-Coding RNA Signature Predicts Prognosis and Immune Microenvironment for Lung Squamous Cell Carcinoma

10.21203/rs.3.rs-963713/v1 ◽

2021 ◽

Author(s):

Zhiyang Liu ◽

Zhongcheng Xie ◽

Chenxi Zhi ◽

Xiaoyan Lin ◽

Wentao Ma ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Squamous Cell ◽

Prognostic Value ◽

Risk Group ◽

Lung Squamous Cell Carcinoma ◽

High Risk Group ◽

Low Risk ◽

Immune Checkpoints

Abstract Background: Ferroptosis-related lncRNAs (FerLncRNAs) were developed to play a significant role in cancer treatment and prognosis. However, the relationship between FerLncRNAs and Lung squamous cell carcinoma (LUSC) remains unclear.Method: Based on ferroptosis-related differentially expressed lncRNAs in LUSC, we established a prognostic 8-lncRNA signature.Results: 8 Ferroptosis-related lncRNAs (LUCAT1, AL161431.1, AL122125.1, AC104248.1, AC016924.1, MIR3945HG, C10orf55 and AP006545.2) had prognostic value for LUSC by multivariate COX analysis (P<0.05), and possessed significant association with patient outcomes. Kaplan–Meier curves showed an obvious difference in OS that the high-risk group patients exhibited poorer survival than the low-risk group patients. The clinical receiver operating characteristic (ROC) curve and decision curve analysis (DCA) revealed that the ferroptosis-related lncRNAs prognostic signature can (FerRLSig) emerged more outstanding performance than clinical features in predicting the prognosis of LUSC. GSEA revealed that the majority of the novel Ferroptosis-related lncRNAs signature-regulated immune responses and the immune system processes were enriched in the high-risk group. 34 immune checkpoints (ICs) were detected significantly different expression between high-risk and low-risk groups.Conclusion: A novel FerRLSig based on 8 Ferroptosis-related lncRNAs provided important prognostic value for LUSC patients and developed new insights about ferroptosis-related immunotherapy targets in clinic.

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A prognostic model for stratification of stage IB/IIA esophageal squamous cell carcinoma: a retrospective study

BMC Gastroenterology ◽

10.1186/s12876-021-01636-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lei-Lei Wu ◽

Qi-Long Ma ◽

Wei Huang ◽

Xuan Liu ◽

Li-Hong Qiu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Prognostic Score ◽

Training Group ◽

Low Risk ◽

Stage Ib ◽

Ptnm Stage

Abstract Background To explore the postoperative prognosis of esophageal squamous cell carcinoma (ESCC) patients with stage IB/IIA, using a prognostic score (PS). Methods Stage IB/IIA ESCC patients who underwent esophagectomy from 1999 to 2010 were included. We retrospectively recruited 153 patients and extracted their medical records. Moreover, we analyzed the programmed death ligand-1 (PD-L1) expression of their paraffin tissue. The cohort were randomly divided into a training group (N = 123) and a validation group (N = 30). We selected overall survival (OS) as observed endpoint. Prognostic factors with a multivariable two-sided P < 0.05 met standard of covariate inclusion. Results Univariable and multivariable analyses identified pTNM stage, the number of lymph nodes (NLNs) and PD-L1 expression as independent OS predictors. Primary prognostic score which comprised above three covariates adversely related with OS in two cohorts. PS discrimination of OS was comparable between the training and internal validation cohorts (C-index = 0.774 and 0.801, respectively). In addition, the PS system had an advantage over pTNM stage in the identification of high-risk patients (C-index = 0.774 vs. C-index = 0.570, P < 0.001). Based on PS cutoff, training and validation datasets generated low-risk and high-risk groups with different OS. Our three-factor PS predicted OS (low-risk subgroup vs. high-risk subgroup 60-month OS, 74% vs. 23% for training cohort and 83% vs. 45% for validation cohort). Conclusion Our study suggested a PS for significant clinical stratification of IB/IIA ESCC to screen out subgroups with poor prognosis.

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A TP53 mutation model for the prediction of prognosis and therapeutic responses in head and neck squamous cell carcinoma

BMC Cancer ◽

10.1186/s12885-021-08765-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Congyu Shi ◽

Shan Liu ◽

Xudong Tian ◽

Xiaoyi Wang ◽

Pan Gao

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Head And Neck ◽

Risk Score ◽

Squamous Cell ◽

Risk Group ◽

High Risk Group ◽

Mutation Model ◽

Therapeutic Responses

Abstract Background Tumor protein p53 (TP53) is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSC), and TP53 mutations are associated with inhibited immune signatures and poor prognosis. We established a TP53 mutation associated risk score model to evaluate the prognosis and therapeutic responses of patients with HNSC. Methods Differentially expressed genes between patients with and without TP53 mutations were determined by using data from the HNSC cohort in The Cancer Genome Atlas database. Patients with HNSC were divided into high- and low-risk groups based on a prognostic risk score that was generated from ten TP53 mutation associated genes via the multivariate Cox regression model. Results TP53 was the most common mutant gene in HNSC, and TP53 mutations were associated with immunogenic signatures, including the infiltration of immune cells and expression of immune-associated genes. Patients in the high-risk group had significantly poorer overall survival than those in the low-risk group. The high-risk group showed less response to anti-programmed cell death protein 1 (PD-1) therapy but high sensitivity to some chemotherapies. Conclusion The risk score based on our TP53 mutation model was associated with poorer survival and could act as a specific predictor for assessing prognosis and therapeutic response in patients with HNSC.

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Oolong tea consumption and its interactions with a novel composite index on esophageal squamous cell carcinoma

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2770-7 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Shuang Liu ◽

Zheng Lin ◽

Liping Huang ◽

Huilin Chen ◽

Yanfang Liu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Risk Group ◽

Composite Index ◽

Tea Consumption ◽

Oolong Tea ◽

Increased Risk

Abstract Background No previous study has investigated the association between oolong tea consumption and esophageal squamous cell carcinoma (ESCC), we aim to elucidate the association between oolong tea consumption and ESCC and its joint effects with a novel composite index. Methods In a hospital-based case-control study, 646 cases of ESCC patients and 646 sex and age matched controls were recruited. A composite index was calculated to evaluate the role of demographic characteristics and life exposure factors in ESCC. Unconditional logistic regression was used to calculate the point estimates between oolong tea consumption and risk of ESCC. Results No statistically significant association was found between oolong tea consumption and ESCC (OR = 1.39, 95% CI: 0.94–2.05). However, drinking hot oolong tea associated with increased risk of ESCC (OR = 1.60, 95% Cl: 1.06–2.41). Furthermore, drinking hot oolong tea increased ESCC risk in the high-risk group (composite index> 0.55) (OR = 3.14, 95% CI: 1.93–5.11), but not in the low-risk group (composite index≤0.55) (OR = 1.16, 95% CI: 0.74–1.83). Drinking warm oolong tea did not influence the risk of ESCC. Conclusions No association between oolong tea consumption and risk of ESCC were found, however, drinking hot oolong tea significantly increased the risk of ESCC, especially in high-risk populations.

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