Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.

BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

7-Dehydrocholesterol dictates ferroptosis sensitivity.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression.

BACKGROUND: UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear. METHODS: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses. RESULTS: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression. CONCLUSIONS: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.

Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.

circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer.

BACKGROUND: Circular RNAs (circRNAs) generated by back-splicing of precursor mRNAs (pre-mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. METHODS: circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull-down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). RESULTS: Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial-mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. CONCLUSIONS: These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.

Evaluation of Traditional Prognostic Factors for Stage I-III Colorectal Cancer Patients Who Survived for Over Five Years After Surgery.

The aim of this study was to explore the prognostic factors in stage I-III colorectal cancer (CRC) patients who had survived for over five years. A total of 9754 stage I-III CRC patients who received curative surgery in the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center were enrolled in this study. Of them, 3640 patients had survived for over five years after surgery. Univariate and multivariate Cox regression analyses were performed in the entire cohort and those who had survived for over five years. Compared with patients in the entire cohort, patients who had survived for over five years were more likely to be younger, have less disease of signet ring cell histology, perineural invasion and vascular invasion, more well differentiated tumors and stage I disease. In the entire cohort, increased age, signet ring cell, poor differentiation, more advanced pathological stage, perineural invasion and vascular invasion were inversely associated with disease-free survival (DFS) and overall survival (OS) using multivariable Cox regression analyses. Only age, pathological stage and perineural invasion remained significant in patients who had survived for over five years. Moreover, tumor location was an independent factor for OS in this subgroup. Predictors for prognosis of CRC change over time. Age, pathological stage and perineural invasion deserve more attention among patients who have survived for over five years.

Hollow Dodecahedra Graphene Oxide- Cuprous Oxide Nanocomposites With Effective Photocatalytic and Bactericidal Activity.

In this study, a kind of graphene oxide-cuprous oxide (GO-Cu2O) nanocomposites was fabricated with different morphologies to serve as a photocatalytic material for the degradation of organic/inorganic dyes under visible light and the bactericidal effect against pathogenic bacteria. The GO-Cu2O was prepared with solid cube and hollow dodecahedra morphologies through in-situ synthesis, and characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Raman, Ultraviolet and visible spectrophotometry (UV/vis), and Fourier transform infrared spectroscopy. In comparison with cubic GO-Cu2O, the absorption and degradation efficiency of the GO-Cu2O dodecahedra (GCD) composite in Methyl orange (MO), Rhodamine B (RhB), and phenol was higher owning to the more active sites for the simultaneous dye and light absorption of hollow structure. The antibacterial effect of the GO-Cu2O dodecahedra was examined by the flat colony counting method with an excellent bactericidal effect against pathogenic bacteria. The possible mechanism for the preparation of GCD possessing the enhancement of the visible-light photocatalytic and antibacterial efficiencies were also investigated.

Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.

Clinicopathological Features of Stage I-III Colorectal Cancer Recurrence Over 5 Years After Radical Surgery Without Receiving Neoadjuvant Therapy: Evidence From a Large Sample Study.

Late recurrence (5 or more years) after radical resection of colorectal cancer (CRC) is rare. This study aims to investigate the features of late recurrence in stage I-III CRC. A total of 9,754 stage I-III patients with CRC who underwent radical surgery without receiving neoadjuvant therapy, at the Fudan University Shanghai Cancer Center (FUSCC), were enrolled in this study. These patients were divided into three groups: early recurrence (3 months-2 years), intermediate recurrence (2-5 years), and late recurrence (over 5 years). The median duration of follow-up was 53.5 ± 30.1 months. A total of 2,341 (24.0%) patients developed recurrence. The late recurrence rate was 11.7%. Patients with a higher risk of late recurrence were more likely to be older, to be at the T4 stage, to have a higher degree of colon cancer, to have a lower frequency of signet ring cell carcinoma, to have fewer poorly differentiated tumors, to be at the early stage of CRC, along with less perineural and vascular invasions. Multivariate logistic regression analysis identified age, differentiation, T stage, N stage, perineural, and vascular invasions as independent factors for late recurrence. Late recurrent CRC has some distinctive characteristics. Although recurrence over 5 years after surgery is infrequent, an enhanced follow-up is still needed for the selected patients after 5 years.

Exploration of the Associations of lncRNA Expression Patterns with Tumor Mutation Burden and Prognosis in Colon Cancer.

BACKGROUND: Tumor mutation burden (TMB) is emerging as a new biomarker to monitor the response of cancer patients to immunotherapy. Long non-coding RNAs (lncRNAs) are critical in regulating gene expression and play a significant role in cancer-associated immune responses. However, the association between lncRNA expression patterns and TMB levels and survival outcomes remains unknown in colon cancer. METHODS: In colon cancer patients from The Cancer Genome Atlas Program (TCGA), a multi-lncRNAs based classifier for predicting TMB levels was established using the least absolute shrinkage and selection operator (LASSO) method. The association between classifier index and immune-related characteristics of patients was also investigated. Quantitative polymerase chain reaction (qPCR) was used to verify the expression levels of these lncRNAs in normal and CRC cell lines. RESULTS: The multi-lncRNAs based classifier had ability to predict TMB level of patients with accuracy (AUC= 0.70), and the general applicability of this classifier was proved in the validation set (AUC= 0.71) and the pooled set (AUC= 0.70). The classifier index was related to three immune checkpoints (PD1, PD-L1, and CTLA-4), the infiltration level of immune cells, and immune response-related score (IFN-γ score, gene expression profiles (GEP) score, cytolytic activity (CYT) score and MHC score). A nomogram, which integrates classifier and some common clinical information, was able to predict the overall survival of colon cancer patients accurately. CONCLUSION: LncRNA expression patterns are associated with TMB, which may serve as a classifier to predict the TMB in colon cancer patients. The nomogram could potentially evaluate survival outcomes and provide a reference to better manage colon cancer patients.

A novel epithelial-mesenchymal transition molecular signature predicts the oncological outcomes in colorectal cancer.

Epithelial-mesenchymal transition (EMT), a biological process involving the transformation of epithelial cells into mesenchymal cells, promotes tumour initiation and metastasis. The aim of this study was to construct an EMT molecular signature for predicting colorectal cancer (CRC) prognosis and evaluate the efficacy of the model. The risk scoring system, constructed by log-rank test and multivariate Cox regression analysis according to EMT-related gene expression in CRC patients from TCGA database, demonstrated the highest correlation with prognosis compared with other parameters in CRC patients. The risk scores were significantly correlated with more lymph node metastasis, distal metastasis and advanced clinical stage of CRC. The model was further successfully validated in two independent external cohorts from GEO database. Furthermore, we developed a nomogram to integrate the EMT signature with the pathological stage of CRC, which was found to perform well in predicting the overall survival. Additionally, this risk scoring model was found to be associated with immune cell infiltration, implying a potential role of EMT involved in immunity regulation in tumour microenvironment. Taken together, our novel EMT molecular model may be useful in identifying high-risk patients who need an intensive follow-up and more aggressive therapy, finally contributing to more precise individualized therapeutic strategies.

Proteomic profiling reveals a signature for optimizing prognostic prediction in Colon Cancer.

Previous studies developed prognostic signatures largely depended on transcriptome profiles. The purpose of our present study was to develop a proteomic signature to optimize the evaluation of prognosis of colon cancer patients. The proteomic data of colon cancer patient cohorts were downloaded from The Cancer Proteome Atlas (TCPA). Patients were randomized 3:2 to train set and internal validation set. Univariate Cox regression and lasso Cox regression analysis were performed to identify the prognostic proteins. A four-protein signature was developed to divide patients into a high-risk group and low-risk group with significantly different survival outcomes in both train set and internal validation set. Time-dependent receiver-operating characteristic at 1 year demonstrated that the proteomic signature presented more prognostic accuracy [area under curve (AUC = 0.704)] than the American Joint Commission on Cancer tumor-node-metastasis (AJCC-TNM) staging system (AUC = 0.681) in entire set. In conclusion, we developed a proteomic signature which can improve prognostic accuracy of patients with colon cancer and optimize the therapeutic and follow-up strategies.

Associations of P Score With Real-World Survival Improvement Offered by Adjuvant Chemotherapy in Stage II Colon Cancer: A Large Population-Based Longitudinal Cohort Study.

BACKGROUND: Based on a prognostic scoring system (P score) proposed by us recently, this retrospective large population-based and propensity score-matched (PSM) study focused on predicting the survival benefit of adjuvant CT in stage II disease. METHODS: Patients diagnosed with stage II colon cancer (N = 73397) were identified from the Surveillance, Epidemiology, and End Results database between January 1, 1988 and December 31, 2005 and divided into the CT and non-CT groups. PSM balanced the patient characteristics between the CT and non-CT groups. RESULTS: The magnitude of CSS improvement among patients treated with adjuvant CT was significantly associated with the P score, score 8 [hazard ratio (HR) = 0.580, 95% confidence interval (CI) = 0.323-1.040, P = 0.067] was associated with a much higher increased CSS benefit among patients treated with adjuvant CT as compared to score 2* (*, including scores 0, 1, and 2; HR = 1.338, 95% CI = 1.089-1.644, P = 0.006). CONCLUSIONS: High P scores were demonstrated to be associated with superior survival benefit of adjuvant CT. Therapy decisions of adjuvant CT in stage II colon cancer could be tailored on the basis of tumor biology, patient characteristics and the P score.

Characterization of the fatty acid metabolism in colorectal cancer to guide clinical therapy.

Colorectal cancer (CRC) is one of the most common malignant tumors, with the second-highest mortality of all 36 cancers worldwide. The roles of fatty acid metabolism in CRC were investigated to explore potential therapeutic strategies. The data files were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a prognostic risk score model with fatty acid metabolism-related genes for predicting prognosis in CRC. Patients with a high-risk score had a poorer prognosis in TCGA cohort than those with a low-risk score and were confirmed in the GEO cohort. Further analysis using the "pRRophetic" R package revealed that low-risk patients were more sensitive to 5-fluorouracil. A comprehensive evaluation of the association between prognostic risk score model and tumor microenvironment (TME) characteristics showed that high-risk patients were suitable for activating a type I/II interferon (IFN) response and inflammation-promoting function. Tumor Immune Dysfunction and Exclusion (TIDE) and SubMap algorithm results also demonstrated that high-risk patients are more suitable for anti-CTLA4 immunotherapy. Therefore, the evaluation of the fatty acid metabolism pattern promotes our comprehension of TME infiltration characteristics, thus guiding effective immunotherapy regimens.

The correlation between tumor size, lymph node status, distant metastases and mortality in rectal cancer patients without neoadjuvant therapy.

Tumor size has an effect on decision making for the treatment rectal cancer. Transanal local excision can be selected to remove rectal cancer with favorable histopathological features. It is generally recognized that the risk of lymph node involvement and distant metastases increases as the tumor enlarges. However, the majority of the studies classified patients into two groups using concrete value as a cutoff point. The coarse classification was not sufficient to reveal a correlation between the tumor size and lymph node status or distant metastases across the full range of sizes examined. Between 1988 and 2015, a total of 77,746 patients were diagnosed with first primary rectal cancer who had not received neoadjuvant therapy. These subjects were identified using the Surveillance, Epidemiology and End Results (SEER) database. The association between tumor size, lymph node status, distant metastases and cancer-specific mortality was investigated. Tumor size was examined as a continuous (1-30 mm) and categorical variable (11 size groups; 10-mm intervals). A non-linear correlation between increasing tumor size and the prevalence of lymph node involvement was observed, while a near-positive correlation between tumor size and distant metastases was presented. In addition, the 5-year and 10-year rates of rectal cancer-specific mortality were increased as the tumor enlarged. For small tumors (under 30 mm), a positive correlation was noted between tumor size and lymph node involvement. The clinical value of the tumor size should be reevaluated by exact classification.

Preparation of graphene oxide (GO)/lanthanum coordination polymers for enhancement of bactericidal activity.

In this study, graphene oxide/lanthanum coordination polymer (GLCP) nanocomposites are prepared and their bactericidal activities against seven typical Pathogenic bacteria are evaluated. The GLCPs are fabricated through the electrostatic self-assembly of La ions on negatively charged graphene oxide (GO), followed by the stabilization of π-π stacking to ensure the formation of lanthanum coordination polymers on the GO surface. The morphologies and structures of the synthesized GLCPs are characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). Moreover, the bactericidal effects of the well-coordinated GLCPs are investigated using the zone of inhibition and flat colony counting methods, as well as by determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The five GLCPs synthesized in this study exhibit broad-spectrum antibacterial activities against seven typical Pathogenic bacteria. We believe that our study could serve as a starting point to prepare bactericidal materials for further applications.

A Novel Seventeen-Gene Metabolic Signature for Predicting Prognosis in Colon Cancer.

A metabolic disorder is considered one of the hallmarks of cancer. Multiple differentially expressed metabolic genes have been identified in colon cancer (CC), and their biological functions and prognostic values have been well explored. The purpose of the present study was to establish a metabolic signature to optimize the prognostic prediction in CC. The related data were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) database, and Gene Expression Omnibus (GEO) combined with GSE39582 set, GSE17538 set, GSE33113 set, and GSE37892 set. The differentially expressed metabolic genes were selected for univariate Cox regression and lasso Cox regression analysis using TCGA and GTEx datasets. Finally, a seventeen-gene metabolic signature was developed to divide patients into a high-risk group and a low-risk group. Patients in the high-risk group presented poorer prognosis compared to the low-risk group in both TCGA and GEO datasets. Moreover, gene set enrichment analyses demonstrated multiple significantly enriched metabolism-related pathways. To sum up, our study described a novel seventeen-gene metabolic signature for prognostic prediction of colon cancer.

Development and validation of a novel epigenetic signature for predicting prognosis in colon cancer.

Epigenetic factors play a critical role in carcinogenesis by imparting a distinct feature to the chromatin architecture. The present study aimed to develop a novel epigenetic signature for evaluating the relapse-free survival of colon cancer patients. Public microarray datasets were acquired from the Gene Expression Omnibus databases: GSE39582, GSE17538, GSE33113, and GSE37892 set. Patients from GSE39582 set were randomized 1:1 into training and internal validation series. Patients were divided into high-risk and low-risk groups in training series based on a set of 11 epigenetic factors (p < .001). The good reproducibility for the prognostic value of the epigenetic signature was confirmed in the internal validation series (p < .001), external validation series (a combination of GSE17538 set, GSE33113 set, and GSE37892 set; p = .018), and entire series (p < .001). Furthermore, a nomogram, which integrated the epigenetic signature, pathological stage, and postoperative chemotherapy, was developed based on the GSE39582 set. The time-dependent receiver operating characteristic curve at 1 year demonstrated that the comprehensive signature presented superior prognostic value than the pathological stage. In conclusion, an epigenetic signature, which could be utilized to divide colon cancer patients into two groups with significantly different risk of relapse, was established. This biomarker would aid in identifying patients who require an intensive follow-up and aggressive therapeutic intervention.

Palliative beam radiotherapy offered real-world survival benefit to metastatic rectal cancer: A large US population-based and propensity score-matched study.

Purpose: Radiotherapy (RT) has been reported to effectively palliate many symptoms of patients with metastatic rectal cancer (mRC). The objective of this study was to evaluate the survival benefit of RT in mRC. Methods: A retrospective population-based cohort study was performed using the Surveillance, Epidemiology, and End Results Program (SEER) database. Patient baseline demographic characteristics between the RT and no-RT groups were compared using Pearson chi-square tests. The outcome of interest was cause-specific survival (CSS). Propensity score (PS) matching and Cox proportional hazards regression analyses were performed to evaluate the prognostic power of variables on CSS. Results: A total of 8851 patients with mRC were identified in the SEER database. Multivariable Cox regression analysis showed that RT was a protective factor in mRC (hazard ratio [HR]= 0.702, 95% confidence interval [CI]=0.665-0.741, p<0.001). In subgroup analysis, multivariate Cox analysis demonstrated that patients of both surgery and no-surgery subgroups treated with RT had better CSS than those not treated with RT (HR=0.654, 95%CI=0.607-0.704, p<0.001 for the surgery group; HR=0.779, 95%CI=0.717-0.847, p<0.001 for the no-surgery group), PS matching resulted in 4170 mRC patients and RT group presented significantly improved survival benefit than no-RT group (22.0 vs. 13.5%, P <0.001). In surgery subgroup after PS matching, in especial, RT group showed more evidently improved survival benefit than no-RT group (30.3 vs. 18.0%, p <0.001). Conclusion: Using the SEER database, we definitely demonstrated that RT was associated with a significant survival advantage beyond the relief of a variety of pelvic symptoms in the setting of mRC. This study strongly supports the use of RT in selected patients with mRC, especially in patients who have undergone surgery. More studies need to be conducted to accurately define the role of RT in mRC.