Clinical Outcome In Colorectal Cancer Research Articles

Identification and functional analysis of lncRNAs and mRNAs between tumorigenesis and metastasis in CRC.

The role of long non-coding RNAs (lncRNAs) in colorectal cancer (CRC) tumorigenesis and metastasis remains poorly characterized. The aim of this study was to identify novel lncRNAs and their functions in CRC progression. Through microarray analysis of paired normal colorectal mucosa (NM), primary tumor (PT), and metastatic lymph node (MLN) tissues, lncRNA and mRNA expression patterns were identified. Further bioinformatic analyses were performed to compare the biological functions of lncRNAs between tumorigenesis and metastasis of CRC, which was further verified by TCGA-COAD and GSE82236. The expression of lncRNA MIR29B2CHG93 in paired CRC tissues was detected in a cohort of CRC patients. The effects of lncRNA MIR29B2CHG93 on proliferation, migration, and invasion were determined by in vitro experiments. We found that tumorigenesis-associated lncRNAs predominantly participated in the regulation of the EMT/P53/PI3K-Akt/KRAS signaling pathway as well as the processes related to cell cycle and cell mitosis, while metastasis-associated lncRNAs mainly regulated blood vessel morphogenesis and immune-related biological processes. Compared to the TCGA and GSE datasets, seven tumorigenesis-associated lncRNAs and eight metastasis-associated lncRNAs were identified. LncRNA MIR29B2CHG93 knockdown remarkably suppressed tumor growth and metastasis in vitro, which acted as a tumor promoter in CRC. The lncRNA MIR29B2CHG93 was significantly upregulated in CRC tissues and was indicator of unfavorable clinical outcome in CRC. These results revealed novel lncRNAs that provide new insights for an in-depth understanding of CRC progression. In particular, this study identified a novel lncRNA MIR29B2CHG93 in CRC progression, which might be a potential biomarker for diagnosis, prognosis and metastasis-prediction in CRC.

The prognostic role of miR-31 in colorectal cancer: the results of a meta-analysis of 4720 patients.

Aims: To study the association between miR-31 expression and clinical outcomes in colorectal cancer. Methods: A systematic search was performed and 16 studies were found eligible. To calculate the combined hazard ratio (HR), the DerSimonian and Laird random-effects model was used. Results: Pooled analysis revealed significant associations between high miR-31 expression and poor overall (HR: 0.68; 95% CI: 0.47-0.97; I2: 68.6%) and progression-free survival (HR: 0.49; 95% CI: 0.33-0.73; I2: 81.1%). High expressers were more likely to have a BRAF mutation. Therapeutic regimen and the mutational status significantly affected the observed associations. Conclusion: We identified that high miR-31 expression is associated with poor overall survival and progression-free survival and has a significant predictive value for anti-EGFR response.

Identification of a novel immune signature for optimizing prognosis and treatment prediction in colorectal cancer.

Background: Globally, colorectal cancer (CRC) is one of the most lethal malignant diseases. However, the currently approved therapeutic options for CRC failed to acquire satisfactory treatment efficacy. Tailoring therapeutic strategies for CRC individuals can provide new insights into personalized prediction approaches and thus maximize clinical benefits.Methods: In this study, a multi-step process was used to construct an immune-related genes (IRGs) based signature leveraging the expression profiles and clinical characteristics of CRC from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. An integrated immunogenomic analysis was performed to determine the association between IRGs with prognostic significance and cancer genotypes in the tumor immune microenvironment (TIME). Moreover, we performed a comprehensive in silico therapeutics screening to identify agents with subclass-specific efficacy.Results: The established signature was shown to be a promising biomarker for evaluating clinical outcomes in CRC. The immune risk score as calculated by this classifier was significantly correlated with over-riding malignant phenotypes and immunophenotypes. Further analyses demonstrated that CRCs with low immune risk scores achieved better therapeutic benefits from immunotherapy, while AZD4547, Cytochalasin B and S-crizotinib might have potential therapeutic implications in the immune risk score-high CRCs.Conclusions: Overall, this IRGs-based signature not only afforded a useful tool for determining the prognosis and evaluating the TIME features of CRCs, but also shed new light on tailoring CRCs with precise treatment.

Tumor budding in colorectal cancer-Information for clinical use and instructions for practical evaluation

HintergrundBei einzelnen Patienten mit kolorektalen Karzinomen (CRC) zeigt sich ein schlechter klinischer Verlauf innerhalb desselben UICC-Stadiums (Union for International Cancer Control). Die Identifizierung von zusätzlichen Risikofaktoren ist daher notwendig, um eine optimale Therapieplanung zu erreichen.FragestellungIn welchen Situationen kann Tumor Budding die klinische Therapieentscheidung beeinflussen und wie sollte die standardisierte Auswertung erfolgen?Material und MethodeAktuelle Publikationen zum Thema Tumor Budding werden mit Fokus auf die praktische Anwendung und potenzielle Problemfälle in der Bestimmung des Tumor Buddings erläutert.ErgebnisseTumor Budding ist ein signifikanter Risikofaktor für einen schlechteren Verlauf des CRC und kann bei pT1-Karzinomen sowie Stadium-II-Karzinomen die Behandlung beeinflussen. Die Auswertung wurde durch die International Tumor Budding Consensus Conference (ITBCC) 2016 standardisiert und ist in der Praxis anwendbar. Schwierigkeiten in der Anwendung können durch die Kenntnis von potenziellen Problemfällen vermieden werden.

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer.

Background: Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE.Methods: Data from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients’ prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining.Results: IVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3+ TILs in the stromal region, as well as fewer CD8+ TILs in both stromal and tumoral regions relative to those without IVE.Conclusion: IVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

Identification of tumor microenvironment-related prognostic genes in colorectal cancer based on bioinformatic methods

Colorectal cancer (CRC) ranks fourth among the deadliest cancers globally, and the progression is highly affected by the tumor microenvironment (TME). This study explores the relationship between TME and colorectal cancer prognosis and identifies prognostic genes related to the CRC microenvironment. We collected the gene expression data from The Cancer Genome Atlas (TCGA) and calculated the scores of stromal/immune cells and their relations to clinical outcomes in colorectal cancer by the ESTIMATE algorithm. Lower immune scores were significantly related to the malignant progression of CRC (metastasis, p = 0.001). We screened 292 differentially expressed genes (DEGs) by dividing CRC cases into high and low stromal/immune score groups. Functional enrichment analyses and protein–protein interaction (PPI) networks illustrated that these DEGs were closely involved in immune response, cytokine–cytokine receptor interaction, and chemokine signaling pathway. Six DEGs (FABP4, MEOX2, MMP12, ERMN, TNFAIP6, and CHST11) with prognostic value were identified by survival analysis and validated in two independent cohorts (GSE17538 and GSE161158). The six DEGs were significantly related to immune cell infiltration levels based on the Tumor Immune Estimation Resource (TIMER). The results might contribute to discovering new diagnostic and prognostic biomarkers and new treatment targets for colorectal cancer.

Integrin β7 Inhibits Colorectal Cancer Pathogenesis via Maintaining Antitumor Immunity.

Immune cell infiltration is important for predicting the clinical outcomes of colorectal cancer. Integrin β7 (ITGB7), which is expressed on the surface of leukocytes, plays an essential role in the homing of immune cells to gut-associated lymphoid tissue and facilitating the retention of lymphocytes in gut epithelium; however, its role in colorectal cancer pathogenesis is poorly explored. Here, we found that the number of β7+ cells decreased significantly in tumor tissue compared with adjacent normal tissue. β7 expression decreased in tumor-derived compared with normal tissue-derived CD8+ T cells. With bulk RNA expression data from public platforms, we demonstrated that higher ITGB7 expression correlated with longer patient survival, higher cytotoxic immune cell infiltration, lower somatic copy-number alterations, decreased mutation frequency of APC and TP53, and better response to immunotherapy. The possible cell-cell interactions mediated by ITGB7 and its ligands MAdCAM-1, VCAM-1, and CDH1 were investigated using public single-cell RNA sequencing data. ITGB7 deficiency led to exaggerated tumorigenesis and progression in both Apcmin /+ spontaneous and MC38 orthotopic models of colorectal cancer, which could be due to a reduced infiltration of activated CD8+ T cells, effector memory CD8+ T cells, IFNγ+ CD8+ T cells, IFNγ+ natural killer cells, CD103+ dendritic cells, and other immune cell subsets that are essential players in antitumor immunity. In conclusion, our data revealed that ITGB7 could inhibit the tumorigenesis and progression of colorectal cancer by maintaining antitumor immunity.

Role of Chronic Inflammatory Ratios in Predicting Recurrence of Resected Patients with Stage I-III Mucinous Colorectal Adenocarcinoma.

BackgroundCancer-related inflammation is the main cause of the progression of mucinous colorectal adenocarcinoma (MCA). Circulating fibrinogen-to-pre-albumin ratio (FPR) is associated with the clinical outcome in colorectal cancer (CRC). However, the prognostic role of FPR and which is the best inflammatory prognostic biomarker within MCA remain unknown.MethodsWe enrolled 157 patients with stage I–III MCA in this study. Kaplan-Meier curve, Cox regression, and time-dependent receiver operation characteristic curve analysis were performed to assess the prognostic value and efficacy of the neutrophil-to-albumin ratio (NAR), neutrophil-to-pre-albumin ratio (NPAR), albumin-to-alkaline phosphatase ratio (AAPR), albumin-to-globulin ratio (AGR), albumin-to-fibrinogen ratio (AFR), and FPR in these patients.ResultsWe found that NAR, NPAR, and FPR were significantly associated with unsatisfactory recurrence-free survival (RFS) in patients with stage I–III MCA, and the predicted efficacy of FPR was superior to that of the other two inflammatory biomarkers. Moreover, patients with a high combined TNM-CA199-FPR score had worse outcomes, with a high predicted efficacy of up to 0.779 (0.703–0.856). Using FPR, the patient was monitored for the recurrence up to two months earlier than that achieved using the common imaging techniques (4 vs 6 median months) in stage I–III MCA patients undergoing radical resection.ConclusionFPR is the preferred inflammatory biomarker and commonly used for predicting and monitoring recurrence in stage I–III MCA patients. The combined TNM-CA199-FPR score is an economical, simple, effective, and independent prognostic factor for localized disease.

Stathmin expression in metastatic colorectal cancer.

To evaluate the relationship between stathmin expression and clinical outcome in colorectal cancer (CRC). Stathmin is a phosphoprotein involved in the regulation of microtubule dynamics and integration of intracellular signaling pathways. Stathmin has been implicated in the tumorigenesis of several cancers and is a potential therapeutic target. Stathmin expression was evaluated in 25 metastatic CRC (mCRC) patients by immunohistochemistry (IHC). Ki67 IHC and TUNEL assay were also evaluated in mCRC for cell proliferation and apoptosis. High expression of stathmin was correlated with CRC metastasis (p = .0084), and significantly worse overall survival (OS) in CRC patients (p = .036). There was a significant increase in cell proliferation and a decrease in apoptosis in liver metastasis compared with CRC primary tumors as determined by Ki67 IHC and TUNEL assay (p < .0001). We also observed a significant positive correlation between stathmin level and cell proliferation in both CRC primary tumor and liver metastasis (p = .0429 to 0.0451; r = .4236 to .4288). Stathmin expression correlated with worse patient prognosis in mCRC patients and positively correlated with increased cell proliferation. Together, our findings indicate stathmin as a novel potential marker for increased risk of CRC-specific mortality and identify stathmin as an attractive therapeutic target for the treatment of mCRC.

Stromal WNTer Keeps the Tumor Cold and Drives Metastasis

Carcinoma-associated fibroblast (CAF) infiltration confers poor clinical outcomes in colorectal cancer (CRC) through mechanisms that are still unclear. In this issue of Developmental Cell, Kasashima etal. report that loss of PKCζ engenders a SOX2/SFRP2-positive CAF subpopulation that increases CRC aggressiveness by creating an immunosuppressed environment.

The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer.

Aims:This study investigated the impact of promoter methylation of flouropyrimidine (FP) metabolizing and cyclooxygenase 2 (COX2) genes on their mRNA expression and on the clinical outcome of colorectal cancer (CRC) patients.Methods:Methylation specific-PCR and real time-PCR of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and COX2 were performed at baseline and after 3 and 6 months of FP therapy. Pairwise comparisons were conducted between the subgroups of CRC patients. The event free survival (EFS) and the hazard of progression were estimated by univariate and multivariate analyses.Results:At baseline CRC patients, both TS and TP were overexpressed, in spite of the unmethylation of TS and the full methylation of TP genes. Significant downexpression of DPD and COX2 were associated their promoter’s methylation. At the end of FP therapy, TS, DPD and COX2 were overexpressed by 7.52, 2.88 and 3.45 folds, respectively, while TP was downexpressed by 0.54 fold. However, no change was observed in the methylation status of genes with FP therapy. Pairwise comparisons revealed significant difference in the expression and the methylation status of genes according to the clinicopathological characters of CRC patients either at baseline or after FP therapy. The overexpression of DPD and COX2 genes were indicators for a poor EFS of CRC patients. Also, the high level of COX2 expression was found to be significantly correlated with the hazard of progression (HR = 1.73, 95% CI = 1.02-3.03).Conclusion:The promoter methylation of FP metabolizing and COX2 genes has significant impact on the expression and the treatment outcome of CRC patients.

Single-Cell Atlas of Infiltrating B Cells and Their Clinical Outcomes in Colorectal Cancer

Background: B cells constitute a major component of infiltrating immune cells in colorectal cancer (CRC). However, the characterization of B cells and their clinical significance remain unclear. Methods: We performed single-cell RNA sequencing to identify the features of B cells in the CRC tumor microenvironment (TME), and validated these findings using flow cytometry and multicolor immunofluorescence staining experiments. B cell-related cellular interactions within the TME were estimated using CellChat and in vitro chemotaxis assay. We then derived gene signatures to construct TME compositions for The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) dataset using the single sample gene set enrichment analysis (ssGSEA) method and unsupervised consensus clustering analysis was employed to identify four colon immune classes (CICs). Finally, we reviewed the landscape of gene mutations across these four CICs. Findings: We identified five distinct subtypes of B cells with their marker genes, distribution patterns, and functional properties in the CRC TME. We found an increased ratio of IgG/IgA plasma cells in tumor sites compared with adjacent normal mucosal tissue. In addition, the CXCL13-producing CD8+ T cells in the tumor tissue could recruit tertiary lymphoid structure (TLS) B cells and CCL28-CCR10 axis are pivotal for IgG plasma cell migration to the intratumor tissue. Finally, we identified four distinct CICs (CIC: A–D) and found that CD20+ B cells within TLS were enriched in one immune-inflamed or hot tumor group (CIC-D). This B cell-rich group, characterized by strong antigen presentation, IgG plasma cell accumulation, microsatellite instability-high (MSI-H) and high tumor mutation burden (TMB-H), as well as immunosuppressive property in particular, might become a potential predictive biomarker for future immunotherapy. Interpretation: Our analysis provides deep insight into infiltrating B cells and their potential clinical implications for immunotherapy in colorectal cancer. Funding Information: This study was financially supported by project grants from the Medical System of Shanghai Minhang District (grant number 2020MWDXK02). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Ethical Committee of The Fifth People’s Hospital of Shanghai, Fudan University. All animal experiment were conducted under the approved protocol Guidelines for the Care and Use of Laboratory Animals.

Genetic variations in microRNA-binding sites of solute carrier transporter genes as predictors of clinical outcome in colorectal cancer.

One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.

Mesenchymal and Phosphatase of Regenerating Liver-3 Status in Circulating Tumor Cells May Serve as a Crucial Prognostic Marker for Assessing Relapse or Metastasis in Postoperative Patients With Colorectal Cancer

INTRODUCTION:Circulating tumor cells (CTCs) and phosphatase of regenerating liver-3 (PRL-3) have been considered to be significant prognostic indicators in metastatic colorectal cancer (CRC). This study discusses the prognostic significance of mesenchymal CTCs with PRL-3 (M+ PRL-3+ CTCs) in postoperative patients with CRC.METHODS:We detected CTC subtypes (including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs) and PRL-3 in CTCs from the peripheral blood samples of 156 patients. Receiver operating characteristic curve analysis, Kaplan-Meier analysis, and Cox proportional hazards regression analysis were performed to identify the prognostic value of mesenchymal CTCs with PRL-3+. Immunohistochemistry was used to detect the expression of PRL-3 in tumor tissues from some of the patients to explore the connection between CTCs and tissues.RESULTS:All CTCs were positive in all samples, both mesenchymal CTCs and PRL-3–positive cells. The count of mesenchymal and PRL-3+ CTCs was significantly associated with recurrence, and the optimal cutoff value was 2 (area under the curve = 0.690, P < 0.001). In addition, these patients had a significantly shorter median disease-free survival than those who did not fulfill the criteria (8.5 vs 24 months, P < 0.001) according to multivariable and multinomial logistic regression. Immunohistochemistry was applied to explore the associations between PRL-3 expression and significant prognostic risk factors, including recurrence (R = 0.566; P < 0.001), and M+ PRL-3+ status in CTCs (R = 0.452; P = 0.001).DISCUSSION:The status of M+ PRL-3+ in CTCs may serve as a crucial prognostic marker for assessing clinical outcomes in CRC.

Analysis of DNA methylation-driven genes for predicting the prognosis of patients with colorectal cancer.

Aberrant promoter methylation and ensuing abnormal gene expression are important epigenetic mechanisms that contribute to colorectal oncogenesis. Yet, the prognostic significance of such methylation-driven genes in colorectal cancer (CRC) remains obscure. Herein, a total of 181 genes were identified as the methylation-driven molecular features of CRC by integrated analysis of the expression profiles and the matched DNA methylation data from The Cancer Genome Atlas (TCGA) database. Among them, a five-gene signature (POU4F1, NOVA1, MAGEA1, SLCO4C1, and IZUMO2) was developed as a risk assessment model for predicting the clinical outcomes in CRC. The Kaplan–Meier analysis and Harrell’s C index demonstrated that the risk assessment model significantly distinguished the patients in high or low-risk groups (p-value < 0.0001 log-rank test, HR: 2.034, 95% CI: 1.419-2.916, C index: 0.655). The sensitivity and specificity were validated by the receiver operating characteristic (ROC) analysis. Furthermore, different pharmaceutical treatment responses were observed between the high-risk and low-risk groups. Indeed, the methylation-driven gene signature could act as an independent prognostic evaluation biomarker for assessing the OS of CRC patients and guiding the pharmaceutical treatment. Compared with known biomarkers, the methylation-driven gene signature could reveal cross-omics molecular features for improving clinical stratification and prognosis.

Correlation of PRL3 expression with colorectal cancer progression.

To evaluate the relationship between phosphatase of regenerating liver 3 (PRL3) expression and clinical outcome in colorectal cancer (CRC). PRL3, a protein tyrosine phosphatase functions as one of the key regulatory enzymes of various signal transduction pathways. PRL3 is highly expressed in a majority of cancers and is a novel potential therapeutic target. PRL3 expression was evaluated by immunohistochemistry in 167 patients with CRC, 37 patients with no disease, and 26 patients with metastatic CRC (mCRC). Phosphorylated Akt at serine 473 (p-Akt S473) expression was also evaluated by immunohistochemistry in mCRC patients. High expression of PRL3 was correlated with CRC progression, and every one unit increase in PRL3 level contributed to an increase in the rate of death by 1%-1.7%. PRL3 expression was significantly higher in liver metastases compared with primary tumors and showed a significant positive correlation with the expression level of p-Akt S473. PRL3 expression levels associated with CRC progression and metastasis, and positively correlated with activated Akt level in mCRC. Together, these findings indicated that PRL3 might be a potential marker for increased risk of CRC-specific tumor burden and identify PRL3 as an attractive therapeutic target for mCRC treatment.

Prognostic Factors Involved in the Epithelial-Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis.

Simple SummaryMetastasis is responsible for most of the deaths related to cancer patients. One of the hypotheses that explains the initiation of metastasis is a process called epithelial-to-mesenchymal transition (EMT), in which tumor cells change shape and acquire more aggressive properties that allows them to escape from the tumor and invade other organs. This also occurs in colorectal cancer (CRC), one of the most diagnosed types of cancer worldwide. During the past years, many scientists have discovered that certain molecules or biomarkers participating in this EMT process are able to predict the severity of the cancer and this is helping clinicians to manage treatments. Nevertheless, we think that all this information needs a detailed revision because a lot of biomarkers have been described but have not been analyzed whether they interact with each other in the same mechanism or not. Herein, we performed a bibliographic revision on this topic and identified a great number of biomarkers participating in oxidative stress, a cellular phenomenon that could have a role on the patient’s prognosis because its presence or absence on the patient’s tumor or blood had an influence on survival. Our findings suggest that oxidative stress deserves further study to understand metastasis better and to predict prognosis in a more efficient way.Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases. Meta-analysis was performed for those markers appearing in minimum three works with a total number of 8656 participants. The rest were enlisted and subjected to functional enrichment. We identified nine clinical biomarkers and 73 EMT-related molecular biomarkers associated to OS and/or PFS in CRC. The significant enrichment of biomarkers found involved in cellular oxidoreductase activity suggests that ROS generation plays an active role in the EMT process. Clinical practice needs new biomarkers with a reliable prognostic value able to predict clinical outcomes in CRC. Our integrative work supports the role of oxidative stress in tumorigenesis and EMT progress highlighting the importance of deciphering this specific mechanism to get a better understanding of metastasis.

Immune scores in colorectal cancer: Where are we?

There is growing evidence that the immune system may prevent the occurrence, growth and metastatic diffusion of colorectal cancer (CRC). The role played by the adaptive immune response at the tumour site is critical in the balance between tumour invasion and defence against cancer. Recent data have shown that the evaluation of this immune response may help to define the prognosis and possibly the treatment of localised CRC as well as metastatic CRC. Tumour infiltrates with T cells (CD3+), cytotoxic T cells (CD8+)and memory T cells (CD45RO+) are the immune parameters most consistently and strongly associated with good clinical outcome in CRC. Several scoring systems have been developed, including the Immunoscore®, based on the immunohistochemical determination with a digital image analysis system of the density of CD3+ and CD8+ lymphocytes in the centre and the invasive margin of the tumour. This review will focus on the different immunoscoring systems developed in CRC, their performance, their limitations and their potential for improving patients' care in the future.

A Novel Model Based on CXCL8-Derived Radiomics for Prognosis Prediction in Colorectal Cancer.

Introduction: Prognosis prediction is essential to improve therapeutic strategies and to achieve better clinical outcomes in colorectal cancer (CRC) patients. Radiomics based on high-throughput mining of quantitative medical imaging is an emerging field in recent years. However, the relationship among prognosis, radiomics features, and gene expression remains unknown.Methods: We retrospectively analyzed 141 patients (from study 1) diagnosed with CRC from February 2018 to October 2019 and randomly divided them into training (N = 99) and testing (N = 42) cohorts. Radiomics features in venous phase image were extracted from preoperative computed tomography (CT) images. Gene expression was detected by RNA-sequencing on tumor tissues. The least absolute shrinkage and selection operator (LASSO) regression model was used for selecting imaging features and building the radiomics model. A total of 45 CRC patients (study 2) with immunohistochemical (IHC) staining of CXCL8 diagnosed with CRC from January 2014 to October 2018 were included in the independent testing cohort. A clinical model was validated for prognosis prediction in prognostic testing cohort (163 CRC patients from 2014 to 2018, study 3). We performed a combined radiomics model that was composed of radiomics score, tumor stage, and CXCL8-derived radiomics model to make comparison with the clinical model.Results: In our study, we identified the CXCL8 as a hub gene in affecting prognosis, which is mainly through regulating cytokine–cytokine receptor interaction and neutrophil migration pathway. The radiomics model incorporated 12 radiomics features screened by LASSO according to CXCL8 expression in the training cohort and showed good performance in testing and IHC testing cohorts. Finally, the CXCL8-derived radiomics model combined with tumor stage performed high ability in predicting the prognosis of CRC patients in the prognostic testing cohort, with an area under the curve (AUC) of 0.774 [95% confidence interval (CI): 0.674–0.874]. Kaplan–Meier analysis of the overall survival probability in CRC patients stratified by combined model revealed that high-risk patients have a poor prognosis compared with low-risk patients (Log-rank P < 0.0001).Conclusion: We demonstrated that the radiomics model reflected by CXCL8 combined with tumor stage information is a reliable approach to predict the prognosis in CRC patients and has a potential ability in assisting clinical decision-making.

Association of XPD Lys751Gln gene polymorphism with susceptibility and clinical outcome of colorectal cancer in Pakistani population: a case-control pharmacogenetic study.

XPD Lys751Gln polymorphism may modulate inter-individual variation in repair capacity of DNA, which may enhance a person's susceptibility to develop colorectal cancer (CRC). The analysis of XPD Lys751Gln polymorphism may provide important information for identifying high-risk individuals and for selecting the most appropriate treatment for poor prognostic CRC patients. The overall objective was to find out the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer and the ultimate clinical outcomes. In this study a total of 300 subjects (CRC and Controls), were genotyped for XPD Lys751Gln. Using PCR-RFLP methods, the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer was studied. In addition to overall risk assessment, genotyping results were also investigated with respect to the lifestyle risk factors, patients treated with oxaliplatin-based chemotherapy and clinicopathological characteristics. The overall correlation between the XPD Lys751Gln genetic variation and the CRC risk was observed to be significant with both the homozygous variant genotype Gln/Gln as well as heterozygous genotype Lys/Gln being associated with the increased risk of CRC. Additional stratified analyses revealed that XPD Lys751Gln variants remarkably increased risk of CRC in males and younger individuals (≤ 50years), Naswar users (8.09-fold) and high intake of red meat. Our findings suggest that the relationship between the XPD Lys751Gln variants and lifestyle factors modulates the risk for CRC in Pakistani population.