scholarly journals Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qin Dang ◽  
Zaoqu Liu ◽  
Shengyun Hu ◽  
Zhuang Chen ◽  
Lingfang Meng ◽  
...  

Colorectal cancer (CRC), a seriously threat that endangers public health, has a striking tendency to relapse and metastasize. Redox-related signaling pathways have recently been extensively studied in cancers. However, the study and potential role of redox in CRC remain unelucidated. We developed and validated a risk model for prognosis and recurrence prediction in CRC patients via identifying gene signatures driven by redox-related signaling pathways. The redox-driven prognostic signature (RDPS) was demonstrated to be an independent risk factor for patient survival (including OS and RFS) in four public cohorts and one clinical in-house cohort. Additionally, there was an intimate association between the risk score and tumor immune infiltration, with higher risk score accompanied with less immune cell infiltration. In this study, we used redox-related factors as an entry point, which may provide a broader perspective for prognosis prediction in CRC and have the potential to provide more promising evidence for immunotherapy.

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian-yu Shi ◽  
Yan-yan Bi ◽  
Bian-fang Yu ◽  
Qing-feng Wang ◽  
Dan Teng ◽  
...  

Despite extensive research, the exact mechanisms involved in colorectal cancer (CRC) etiology and pathogenesis remain unclear. This study aimed to examine the correlation between tumor-associated alternative splicing (AS) events and tumor immune infiltration (TII) in CRC. We analyzed transcriptome profiling and clinical CRC data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq and Innate databases, respectively to develop and validate a risk model of differential AS events and subsequently a TII risk model. We then conducted a two-factor survival analysis to study the association between TII and AS risk and evaluated the associations between immune signatures and six types of immune cells based on the TIMER database. Subsequently, we studied the distribution of six types of TII cells in high- and low-risk groups for seven AS events and in total. We obtained the profiles of AS events/genes for 484 patients, which included 473 CRC tumor samples and 41 corresponding normal samples, and detected 22581 AS events in 8122 genes. Exon Skip (ES) (8446) and Mutually Exclusive Exons (ME) (74) exhibited the most and fewest AS events, respectively. We then classified the 433 patients with CRC into low-risk (n = 217) and high-risk (n = 216) groups based on the median risk score in different AS events. Compared with patients with low-risk scores (mortality = 11.8%), patients with high-risk scores were associated with poor overall survival (mortality = 27.6%). The risk score, cancer stage, and pathological stage (T, M, and N) were closely correlated with prognosis in patients with CRC (P < 0.001). We identified 6479 differentially expressed genes from the transcriptome profiles of CRC and intersected 468 differential immune-related signatures. High-AS-risk and high-TII-risk predicted a poor prognosis in CRC. Different AS types were associated with different TII risk characteristics. Alternate Acceptor site (AA) and Alternate Promoter (AP) events directly affected the concentration of CD4T cells, and the level of CD8T cells was closely correlated with Alternate Terminator (AT) and Exon Skip (ES) events. Thus, the concentration of CD4T and CD8T cells in the CRC immune microenvironment was not specifically modulated by AS. However, B cell, dendritic cell, macrophage, and neutrophilic cell levels were strongly correlated with AS events. These results indicate adverse associations between AS event risk levels and immune cell infiltration density. Taken together, our findings show a clear association between tumor-associated alternative splicing and immune cell infiltration events and patient outcome and could form a basis for the identification of novel markers and therapeutic targets for CRC and other cancers in the future.


2021 ◽  
Vol 14 ◽  
Author(s):  
Lara J. Bou Malhab ◽  
Wael M. Abdel-Rahman

: The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tuo Liang ◽  
Jiarui Chen ◽  
GuoYong Xu ◽  
Zide Zhang ◽  
Jiang Xue ◽  
...  

AbstractWe established a relationship among the immune-related genes, tumor-infiltrating immune cells (TIICs), and immune checkpoints in patients with osteosarcoma. The gene expression data for osteosarcoma were downloaded from UCSC Xena and GEO database. Immune-related differentially expressed genes (DEGs) were detected to calculate the risk score. “Estimate” was used for immune infiltrating estimation and “xCell” was used to obtain 64 immune cell subtypes. Furthermore, the relationship among the risk scores, immune cell subtypes, and immune checkpoints was evaluated. The three immune-related genes (TYROBP, TLR4, and ITGAM) were selected to establish a risk scoring system based on their integrated prognostic relevance. The GSEA results for the Hallmark and KEGG pathways revealed that the low-risk score group exhibited the most gene sets that were related to immune-related pathways. The risk score significantly correlated with the xCell score of macrophages, M1 macrophages, and M2 macrophages, which significantly affected the prognosis of osteosarcoma. Thus, patients with low-risk scores showed better results with the immune checkpoints inhibitor therapy. A three immune-related, gene-based risk model can regulate macrophage activation and predict the treatment outcomes the survival rate in osteosarcoma.


2021 ◽  
Vol 14 (8) ◽  
pp. 1151-1159
Author(s):  
Chen-Lu Liao ◽  
◽  
Xing-Yu Sun ◽  
Qi Zhou ◽  
Min Tian ◽  
...  

AIM: To investigate the role of tumor microenvironment (TME)-related long non-coding RNA (lncRNA) in uveal melanoma (UM), probable prognostic signature and potential small molecule drugs using bioinformatics analysis. METHODS: UM expression profile data were downloaded from the Cancer Genome Atlas (TCGA) and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration. The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis (ssGSEA) method, and the immune cell infiltration of a single specimen was evaluated. Finally, the specimens were divided into high and low infiltration groups. The differential expression between the two groups was analyzed using the R package ‘edgeR’. Univariate, multivariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were performed to explore the prognostic value of TME-related lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses were also performed. The Connectivity Map (CMap) data set was used to screen molecular drugs that may treat UM. RESULTS: A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups. Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis. Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements. Among 269 differentially expressed lncRNAs, 69 were up-regulated and 200 were down-regulated. Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age, TNM stage, tumor base diameter, and low and high risk indices had significant prognostic value. We screened the potential small-molecule drugs for UM, including W-13, AH-6809 and Imatinib. CONCLUSION: The prognostic markers identified in this study are reliable biomarkers of UM. This study expands our current understanding of the role of TME-related lncRNAs in UM genesis, which may lay the foundations for future treatment of this disease.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3538-3538
Author(s):  
Ling Zhang ◽  
Jianping Song ◽  
Yiting Wang ◽  
Yaoxu Chen

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD(colon adenocarcinoma, 404 patients)from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15512-e15512
Author(s):  
David A. Drubin ◽  
Anne-Katrin Hess ◽  
Natalie L. Catlett ◽  
Alessandro Di Cara ◽  
Yvonne Wettergren ◽  
...  

e15512 Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3173-3173 ◽  
Author(s):  
Alok A. Khorana ◽  
Kimberly Herman ◽  
Deborah Rubens ◽  
Charles W. Francis

Abstract Abstract 3173 Background: We evaluated the utility of screening for VTE using a previously developed clinical risk score (Khorana et al, Blood 2008) in a prospective cohort of cancer patients initiating outpatient chemotherapy but not receiving thromboprophylaxis. Methods: Cancer patients initiating a new chemotherapy regimen and deemed high-risk based on a predictive risk model (score ≥3) were enrolled on an ongoing prospective cohort study with informed consent. Patients were evaluated with baseline and Q4 (± 1) week serial ultrasonography for upto 16 weeks; additionally, computed tomography scans for restaging were also evaluated for VTE. Results: Of 30 patients enrolled on study, 8 (27%) developed a VTE. This included 5 patients with DVT alone (17%), 1 patient with PE alone (3%) and 2 (7%) with both. Twenty-seven patients underwent a baseline ultrasound. Of these, 3 asymptomatic DVTs were identified (11%). Subsequent ultrasounds were performed in 18 patients at week 4 (0 DVT), 17 patients at week 8 (0 DVT) and 15 patients at week 12 (1 DVT, 7%). An additional two patients developed symptomatic DVT between weeks 1 and 4. Restaging CT scans identified an asymptomatic PE in 1 patient at week 6 and asymptomatic PE in 1 patient at week 9 with subsequent symptomatic DVT at week 10. Conclusions: In a prospective observational study, 27% of cancer outpatients deemed high-risk using a clinical risk score developed VTE, a rate much higher than observed even in hospitalized acutely ill patients. Thus, this study confirms the validity of a previously described risk score. The role of thromboprophylaxis in this population is currently being tested. The value of screening ultrasonography should be considered in high-risk patients based on this risk score. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Qingli Quan ◽  
Xinxin Xiong ◽  
Shanyun Wu ◽  
Meixing Yu

Autophagy plays an important role in cancer. Many studies have demonstrated that autophagy-related genes (ARGs) can act as a prognostic signature for some cancers, but little has been known in low-grade gliomas (LGG). In our study, we aimed to establish a prognostical model based on ARGs and find prognostic risk-related key genes in LGG. In the present study, a prognostic signature was constructed based on a total of 8 ARGs (MAPK8IP1, EEF2, GRID2, BIRC5, DLC1, NAMPT, GRID1, and TP73). It was revealed that the higher the risk score, the worse was the prognosis. Time-dependent ROC analysis showed that the risk score could precisely predict the prognosis of LGG patients. Additionally, four key genes (TGFβ2, SERPING1, SERPINE1, and TIMP1) were identified and found significantly associated with OS of LGG patients. Besides, they were also discovered to be strongly related to six types of immune cells which infiltrated in LGG tumor. Taken together, the present study demonstrated the promising potential of the ARG risk score formula as an independent factor for LGG prediction. It also provided the autophagy-related signature of prognosis and potential therapeutic targets for the treatment of LGG.


2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Feng ◽  
Jiahui Zhao ◽  
Dechao Wei ◽  
Pengju Guo ◽  
Xiaobing Yang ◽  
...  

BackgroundRenal cell carcinoma (RCC) is associated with poor prognostic outcomes. The current stratifying system does not predict prognostic outcomes and therapeutic benefits precisely for RCC patients. Here, we aim to construct an immune prognostic predictive model to assist clinician to predict RCC prognosis.MethodsHerein, an immune prognostic signature was developed, and its predictive ability was confirmed in the kidney renal clear cell carcinoma (KIRC) cohorts based on The Cancer Genome Atlas (TCGA) dataset. Several immunogenomic analyses were conducted to investigate the correlations between immune risk scores and immune cell infiltrations, immune checkpoints, cancer genotypes, tumor mutational burden, and responses to chemotherapy and immunotherapy.ResultsThe immune prognostic signature contained 14 immune-associated genes and was found to be an independent prognostic factor for KIRC. Furthermore, the immune risk score was established as a novel marker for predicting the overall survival outcomes for RCC. The risk score was correlated with some significant immunophenotypic factors, including T cell infiltration, antitumor immunity, antitumor response, oncogenic pathways, and immunotherapeutic and chemotherapeutic response.ConclusionsThe immune prognostic, predictive model can be effectively and efficiently used in the prediction of survival outcomes and immunotherapeutic responses of RCC patients.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Pu Wu ◽  
Jinyuan Shi ◽  
Wei Sun ◽  
Hao Zhang

Abstract Background Pyroptosis is a form of programmed cell death triggered by inflammasomes. However, the roles of pyroptosis-related genes in thyroid cancer (THCA) remain still unclear. Objective This study aimed to construct a pyroptosis-related signature that could effectively predict THCA prognosis and survival. Methods A LASSO Cox regression analysis was performed to build a prognostic model based on the expression profile of each pyroptosis-related gene. The predictive value of the prognostic model was validated in the internal cohort. Results A pyroptosis-related signature consisting of four genes was constructed to predict THCA prognosis and all patients were classified into high- and low-risk groups. Patients with a high-risk score had a poorer overall survival (OS) than those in the low-risk group. The area under the curve (AUC) of the receiver operator characteristic (ROC) curves assessed and verified the predictive performance of this signature. Multivariate analysis showed the risk score was an independent prognostic factor. Tumor immune cell infiltration and immune status were significantly higher in low-risk groups, which indicated a better response to immune checkpoint inhibitors (ICIs). Of the four pyroptosis-related genes in the prognostic signature, qRT-PCR detected three of them with significantly differential expression in THCA tissues. Conclusion In summary, our pyroptosis-related risk signature may have an effective predictive and prognostic capability in THCA. Our results provide a potential foundation for future studies of the relationship between pyroptosis and the immunotherapy response.


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