RESUMO
BACKGROUND: Recurrences are the main reasons for unfavorable outcomes for patients with stage II colorectal cancer (CRC). To obtain a clear understanding of the high-risk factors, further investigation is warranted. The present study aimed to analyze the risk factors associated with postoperative recurrence in patients with stage II CRC. METHODS: Eligible patients with pathologically confirmed stage II CRC were enrolled in the study retrospectively based on a prospectively maintained database from April 2008 to March 2019. The Kaplan-Meier method were used to calculate the overall survival (OS) rate and the cumulative recurrence rate. Univariate and multivariable Cox regression analyses were performed to identify risk factors for recurrence. RESULTS: There were 2515 patients included, of whom 233 (9.3%) developed local or distant recurrence. Recurrence was associated with a significantly worse 5-year OS (45.4% vs. 95.5%, p < 0.0001). The 5-year cumulative recurrence rate was 13.0% in patients with stage II CRC. On multivariable Cox analysis, tumor size (Hazard Ratio (HR) [95% confidence interval (CI)] = 1.79[1.38, 2.33]), preoperative carbohydrate antigen (CA) 125 level (HR [95% CI] = 1.78[1.17, 2.70]), preoperative CA 199 level (HR [95% CI] = 1.56[1.09, 2.22]), and ulcerating tumor (HR [95% CI] = 1.61[1.19, 2.17]) were found to be associated with postoperative recurrence. Adjuvant chemotherapy was associated with a lower cumulative recurrence rate in patients with these risk factors (p = 0.00096). CONCLUSION: The tumor diameter, preoperative CA125 level, preoperative CA199 level, and an ulcerative tumor can predict postoperative recurrence in patients with stage II CRC, and postoperative chemotherapy could reduce the cumulative recurrence rate in patients with these high-risk factors.
Assuntos
Neoplasias Colorretais , Humanos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Colorretais/patologia , Fatores de Risco , Recidiva Local de Neoplasia/patologiaRESUMO
BACKGROUND: With the aging of the population, the burden of elderly gastric cancer (EGC) increases worldwide. However, there is no consensus on the definition of EGC and the efficacy of adjuvant chemotherapy in patients with stage II EGC. Here, we investigated the effectiveness of adjuvant chemotherapy in defined EGC patients. METHODS: We enrolled 5762 gastric cancer patients of three independent cohorts from the Sixth Affiliated Hospital of Sun Yat-sen University (local), the Surveillance, Epidemiology, and End Results (SEER), and the Asian Cancer Research Group (ACRG). The optimal age cutoff for EGC was determined using the K-adaptive partitioning algorithm. The defined EGC group and the efficacy of adjuvant chemotherapy for them were confirmed by Cox regression and Kaplan-Meier survival analyses. Furthermore, gene set variation analyses (GSVA) were performed to reveal pathway enrichment between groups. RESULTS: The optimal age partition value for EGC patients was 75. In the local, SEER, and ACRG cohorts, the EGC group exhibited significantly worse overall survival and cancer-specific survival than the non-EGC group (P < 0.05) and was an independent risk factor. Stratified analyses based on chemotherapy showed that EGC patients derived little benefit from adjuvant chemotherapy. Furthermore, GSVA analysis revealed the activation of DNA repair-related pathways and downregulation of the p53 pathway, which may partially contribute to the observed findings. CONCLUSION: In this retrospective, international multi-center study, 75 years old was identified as the optimal age cutoff for EGC definition, and adjuvant chemotherapy proved to be unbeneficial for stage II EGC patients.
Assuntos
Neoplasias Gástricas , Humanos , Idoso , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Fatores de Risco , Estimativa de Kaplan-Meier , Quimioterapia Adjuvante , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Patients with ulcerative colitis are at an increased risk of developing colorectal cancer with a prolonged disease course. Many studies have shown that alterations in the immune microenvironment play a key role in ulcerative colitis-associated colorectal cancer. Additionally, competing endogenous RNAs have important functions in immunoregulation, affecting inflammation and tumorigenesis. However, the complexity and behavioral characteristics of the competing endogenous RNA immunoregulatory network in ulcerative colitis-associated colorectal cancer remain unclear. We constructed a competing endogenous RNA immunoregulatory network to discover and validate a novel competing endogenous RNA immunoregulatory axis to provide insight into ulcerative colitis-associated colorectal cancer progression. METHODS: The competing endogenous RNA immunoregulatory network was constructed using differential expression analysis, weighted gene co-expression network analysis, and immune-related genes. Cmap was used to identify small-molecule drugs with therapeutic potential in ulcerative colitis-associated colorectal cancer. The ulcerative colitis-associated colorectal cancer-related pathways were identified by gene set variation and enrichment analysis. CIBERSORT, single-sample Gene Set Enrichment Analysis, and xCell were used to evaluate the infiltration of immune cells and screen hub immunocytes. The competing endogenous RNA immunoregulatory axis was identified by correlation analysis. RESULTS: We identified 130 hub immune genes and constructed a competing endogenous RNA immunoregulatory network consisting of 56 long non-coding RNAs, four microRNAs, and six targeted hub immune genes. Four small-molecule drugs exerted potential therapeutic effects by reversing the expression of hub immune genes. Pathway analysis showed that the NF-κB pathway was significantly enriched. Neutrophils were identified as hub immunocytes, and IL6ST was significantly positively correlated with the neutrophil count. In addition, NEAT1 may serve as a competing endogenous RNA to sponge miR-1-3p and promote IL6ST expression. CONCLUSIONS: The competing endogenous RNA immunoregulatory axis may regulate neutrophil infiltration, affecting the occurrence of ulcerative colitis-associated colorectal cancer.
Assuntos
Colite Ulcerativa , Neoplasias Associadas a Colite , MicroRNAs , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Neoplasias Associadas a Colite/genética , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: The clinical characteristics of synchronous colorectal cancer (SCRC) reported in previous studies differ significantly. Furthermore, little is known about the characteristics of early-onset synchronous colorectal cancer (EO-SCRC). The aim of this retrospective study was to identify the clinicopathological characteristics of SCRC and EO-SCRC and define their relevant prognostic factors. METHODS: Patients who underwent surgery for SCRC and primary unifocal colorectal cancer (PCRC) between January 2007 and December 2020 were included in this study. The clinical, histological, and molecular characteristics of the patient's tumours were analysed. The primary endpoint was overall survival (OS). Univariate and multivariate Cox regression analyses were used to assess the association between clinicopathological factors and patient survival. RESULTS: A total of 1554 patients were included in the analysis. Of these, 1132 (72.84%) had PCRC and 422 (27.16%) had SCRC. SCRC occurred more frequently in the elderly (P < 0.001) and in male patients (P = 0.002). The 5-year OS rate was 73.7% ± 2.0% for PCRC and 61.9% ± 3.9% for SCRC (P < 0.05). However, the Cox regression analysis showed that SCRC was not an independent prognostic factor for the prediction of OS. A total of 64 patients (15.17%) in the SCRC group had early-onset colorectal cancer (EOCRC), whereas 257 (22.70%) in the PCRC group had EOCRC (P = 0.001). The proportion of patients with deficient mismatch repair proteins (dMMR) in EO-SCRC subgroup was significantly higher than that in late-onset synchronous colorectal cancer (LO-SCRC) subgroup (23.44% vs. 10.34%, P = 0.006). Patients with EO-SCRC had more TNM stage IV (P < 0.001) and fewer opportunities for radical surgery (79.69% vs. 92.22%, P = 0.007) than those with early-onset primary unifocal colorectal cancer (EO-PCRC). There was no significant difference in 5-year OS between the EO-SCRC and LO-SCRC subgroups (P = 0.091) and between the EO-SCRC and EO-PCRC subgroups (P = 0.094). Multivariate analysis revealed that EOCRC was an independent good prognostic parameter for colorectal cancer (CRC) and SCRC. CONCLUSION: For patients with operative treatment, EO-SCRC is different from LO-SCRC and EO-PCRC. Patients with SCRC show a poorer survival rate than those with PCRC. However, SCRC is not an independent prognostic factor for CRC, whereas EOCRC is a good prognostic factor for CRC and SCRC.
Assuntos
Neoplasias Colorretais , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Humanos , Modelos Logísticos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Intestinal fibrosis is a common complication of Crohn's disease (CD). Adiponectin reportedly exerts anti-inflammatory effects in various disease models, including colitis models. AIMS: In this study, we aimed to determine the effects of adiponectin on intestinal fibrosis and the underlying mechanisms. METHODS: A murine model of intestinal fibrosis was established by administering increasing doses of 2,4,6-trinitrobenzene sulfonic acid to Balb/c mice via enema for 7 weeks. Primary human fibroblasts were isolated from the colon tissues of patients with CD. The fibroblasts were incubated with transforming growth factor (TGF)-ß1 to establish a fibrosis model in vitro. Pathway inhibitors were used to verify the potential signaling pathways involved in the anti-fibrogenic effect of adiponectin. RESULTS: Compared with the normal mesentery, adiponectin expression was significantly increased in the hypertrophic mesentery of patients with CD. Intraperitoneal injection of adiponectin significantly decreased the activity of myeloperoxidase and the expression of pro-inflammatory cytokines (tumor necrosis factor α and interleukin 6) in the colon of fibrosis model mice, whereas the expression of the anti-inflammatory cytokine interleukin 10 was substantially increased. Moreover, adiponectin treatment inhibited colon shortening, decreased colon weight, and reduced fibrotic protein deposition in the model mice. Adiponectin reduced the phosphorylation of Smad2 and collagen deposition induced by TGF-ß1 in primary human intestinal fibroblasts, with an increase in AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, this phenomenon was reversed by the AMPK inhibitor. CONCLUSIONS: Adiponectin can protect against intestinal fibrosis by enhancing the phosphorylation of AMPK and inhibiting the activity of the TGF-ß1/Smad signaling pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , Adiponectina , Doença de Crohn , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/metabolismo , Adiponectina/farmacologia , Animais , Doença de Crohn/patologia , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibrose , Humanos , Camundongos , Fosforilação , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: The therapeutic potential of adipose-derived mesenchymal stromal cells (AMSCs) in the treatment of intestinal fibrosis occured in patients with Crohn's disease (CD) remains unclear. Tumor necrosis factor-stimulated gene 6 (TSG6) protein plays a critical role in inflammation regulation and tissue repair. This study aimed to determine if AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein and explore the underlying mechanisms. METHODS: Two murine models for intestinal fibrosis were established using 2,4,6-trinitrobenzene sulfonic acid in BALB/c mice and dextran sulfate sodium in C57BL/6 mice. Primary human fibroblasts and CCD-18co cells were incubated with transforming growth factor (TGF)-ß1 to build two fibrosis cell models in vitro. RESULTS: Intraperitoneally administered AMSCs attenuated intestinal fibrosis in the two murine models, as evidenced by significant alleviation of colon shortening, collagen protein deposits, and submucosal thickening, and also decrease in the endoscopic and fibrosis scores (P < 0.001). Although intraperitoneally injected AMSCs did not migrate to the colon lesions, high levels of TSG6 expression and secretion were noticed both in vivo and in vitro. Similar to the role of AMSCs, injection of recombinant human TSG6 attenuated intestinal fibrosis in the mouse models, which was not observed with the administration of AMSCs with TSG6 knockdown or TSG6 neutralizing antibody. Mechanistically, TSG6 alleviates TGF-ß1-stimulated upregulation of α-smooth muscle actin (αSMA) and collagen I by inhibiting Smad2 phosphorylation. Furthermore, the expression of TSG6 is lower in intestinal fibrosis tissue of patients with Crohn's disease and can reduce pro-fibrotic protein (αSMA) secretion from primary ileal fibrotic tissue. CONCLUSIONS: AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein, which inhibits Smad2 phosphorylation. TSG6, a novel anti-fibrotic factor, could potentially improve intestinal fibrosis treatments.
Assuntos
Moléculas de Adesão Celular , Doença de Crohn , Modelos Animais de Doenças , Fibrose , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína Smad2 , Animais , Humanos , Células-Tronco Mesenquimais/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Doença de Crohn/terapia , Doença de Crohn/patologia , Doença de Crohn/metabolismo , Camundongos , Proteína Smad2/metabolismo , Masculino , Sulfato de Dextrana , Ácido Trinitrobenzenossulfônico , Tecido Adiposo/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Colo/patologia , Colo/metabolismo , Colite/induzido quimicamente , Colite/terapia , Colite/patologiaRESUMO
BACKGROUND: Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with poorer prognosis in several human malignancies, but their significance in gastric cancer (GC) remains to be clearly defined. Our study aimed to investigate the prognostic value of LVI/PNI in patients with curative resected GC. METHODS: Records of 1488 patients with stage I--III GC and 3327 patients with stage I-III colorectal cancer (CRC) were reviewed retrospectively, and difference in the incidence of LVI/PNI between GC and CRC was compared. Univariate and multivariate analyses were used to evaluate whether LVI/PNI was an independent risk factor for lymph node metastasis (LNM) and overall survival (OS) in GC. RESULTS: Patients with stage I-III GC had a significantly higher incidence of LVI/PNI than patients with stage I-III CRC (50.54% vs. 21.91%, p < 0.001). LVI/PNI was significantly associated with higher CEA, higher CA199, deeper tumor invasion, more lymph node metastasis, and advanced TNM stage in GC ( p < 0.05). Multivariate logistic regression analysis identified LVI/PNI (OR = 2.64, 95%CI: 2.05-3.40, p < 0.001) as an independent risk factor for LNM in GC. The OS rate was significantly lower in the LVI/PNI-positive GC group than that in the LVI/PNI-negative GC group ( p < 0.001). On multivariate Cox regression analysis, LVI/PNI (HR = 1.34, 95%CI: 1.04-1.71, p = 0.023) was an independent prognostic factor for OS in GC. CONCLUSION: GC has a high incidence of LVI/PNI, which was closely associated with disease progression. LVI/PNI could serve as an independent risk factor for LNM and the prognosis of patients with curative resected GC. These findings will be helpful in predicting survival outcomes more accurately and establishing individualized treatment plans.
Assuntos
Neoplasias Colorretais , Neoplasias Gástricas , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Metástase Linfática , Invasividade Neoplásica/patologia , Prognóstico , Neoplasias Colorretais/patologia , Taxa de SobrevidaRESUMO
PURPOSE: Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. METHODS: We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. RESULTS: We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. CONCLUSION: HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.
Assuntos
Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Prognóstico , Estudos Retrospectivos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Taxa de Sobrevida , Neoplasias Colorretais/patologiaRESUMO
Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes ß-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of ß-catenin and subsequent ß-Trcp-mediated proteasomal degradation. In return, stabilized ß-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of ß-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-ß-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated ß-catenin palmitoylation and stabilization and hyperactivates ß-catenin signaling thus promoting CRC progression. Particularly, targeting ß-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit ß-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-ß-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating ß-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or ß-catenin palmitoylation as a viable option for CRC treatment.
RESUMO
BACKGROUND: Lymph node metastasis (LNM) is a critical factor in determining the prognosis of gastric cancer (GC), but its underlying mechanism remains unclear. The tumor mutational burden (TMB) has recently been recognized as a biomarker for predicting prognosis and response to immune checkpoint inhibitors, while mucin 16, cell surface associated (MUC16) is frequently mutated in GC. This study explored whether MUC16 mutation status is associated with TMB, LNM, and prognosis in patients with GC. METHODS: Somatic mutation data were downloaded from three GC cohorts. TMB values were calculated and associations between the TMB and clinical characteristics were analyzed. The mutational landscapes of these three GC cohorts were individually explored and visualized using waterfall diagrams. Univariate logistic regression and Kaplan-Meier survival analysis were performed to screen for mutated genes associated with LNM and overall survival (OS). Associations between MUC16 mutations and TMB, microsatellite instability (MSI), LNM, and tumor microenvironment signatures were explored. RESULTS: TMB was associated with LNM and OS in patients with GC. Analyzing the three GC cohorts (The Cancer Genome Atlas-Stomach Adenocarcinoma, International Cancer Genome Consortium [ICGC]-China, and ICGC-Japan) revealed that MUC16 was one of the most frequently mutated genes in patients with GC. MUC16 mutations were associated with better prognosis, including lower LNM rates and improved OS rates. In addition, MUC16 mutation status was associated with TMB and MSI statuses. Fifteen upregulated and 222 downregulated genes were identified in patients with MUC16 mutations, compared to in those in patients with wild-type MUC16. An altered tumor microenvironment signature was also identified in GC samples with MUC16 mutations; it was characterized by significantly decreased infiltration regarding stromal cells, CD4+ T cells, and macrophages. CONCLUSION: MUC16 mutation status was associated with TMB, microsatellite status, LNM, and survival in patients with GC. These findings may provide new insights into the mechanism of LNM and could act as a signpost for prognostic predictions and immunotherapy guidance for patients with GC.
RESUMO
BACKGROUND: Immune-related genes (IRGs) play important roles in the tumor immune microenvironment and can affect the prognosis of cancer. This study aimed to construct a novel IRG signature for prognostic evaluation of stage II colorectal cancer (CRC). METHODS: Gene expression profiles and clinical data for stage II CRC patients were collected from the Cancer Genome Atlas and Gene Expression Omnibus database. Univariate, multivariate Cox regression, and least absolute shrinkage and selection operator regression were used to develop the IRG signature, namely IRGCRCII. A nomogram was constructed, and the "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts" (CIBERSORT) method was used to estimate immune cell infiltration. The expression levels of genes and proteins were validated by qRT-PCR and immunohistochemistry in 30 pairs of primary stage II CRC and matched normal tissues. RESULTS: A total of 466 patients with stage II CRC were included, and 274 differentially expressed IRGs were identified. Six differentially expressed IRGs were detected and used to construct the IRGCRCII signature, which could significantly stratify patients into high-risk and low-risk groups in terms of disease-free survival in three cohorts: training, test, and external validation (GSE39582). Receiver operating characteristics analysis revealed that the area under the curves of the IRGCRCII signature were significantly greater than those of the OncotypeDX colon signature at 1 (0.759 vs. 0.623), 3 (0.875 vs. 0.629), and 5 years (0.906 vs. 0.698) disease-free survival, respectively. The nomogram performed well in the concordance index (0.779) and calibration curves. The high-risk group had a significantly higher percentage of infiltrated immune cells (e.g., M2 macrophages, plasma cells, resting mast cells) than the low-risk group. Finally, the results of qRT-PCR and immunohistochemistry experiments performed on 30 pairs of clinical specimens were consistent with bioinformatics analysis. CONCLUSION: This study developed and validated a novel immune prognostic signature based on six differentially expressed IRGs for predicting disease-free survival and immune status in patients with stage II CRC, which may reflect immune dysregulation in the tumor immune microenvironment.
RESUMO
BACKGROUND: Recently, a study from our center indicated that the ratio of preoperative carcinoembryonic antigen (CEA) concentration to maximum tumor diameter (DMAX) may be a prognostic marker for patients with rectal cancer. Therefore, the study aimed to evaluate whether this ratio (CEA/DMAX) has prognostic value for patients with stage II colorectal cancer (CRC). METHODS: A prospectively maintained database was searched for patients with pathologically confirmed stage II CRC who underwent surgery between January 2010 and March 2019. Patients were stratified according to the mean CEA/DMAX value into low and high CEA/DMAX groups. Kaplan-Meier, univariable, and multivariable Cox regression analyses were used to evaluate whether the CEA/DMAX could predict overall survival (OS) and disease-free survival (DFS). Nomograms were constructed in terms of the results of multivariable Cox regression analyses. RESULTS: The study included 2,499 patients with stage II CRC. The mean CEA/DMAX value was 2.33 (ng/mL per cm). Kaplan-Meier analyses revealed that, relative to the low CEA/DMAX group, the high CEA/DMAX group had significantly poorer OS (67.31% vs. 85.02%, P<0.001) and DFS (61.41% vs. 77.10%, P<0.001). The multivariable Cox regression analysis revealed that CEA/DMAX independently predicted OS (hazard ratio: 2.58, 95% confidence interval: 1.51-4.38, P<0.001) and DFS (hazard ratio: 1.97, 95% confidence interval: 1.38-2.83, P<0.001). Two simple-to-use nomograms comprising CEA/DMAX, age, T stage, and lymphovascular invasion were developed to predict 1-, 3-, and 5-year rates of OS and DFS among patients with stage II CRC. The nomograms had good performance based on the concordance index, receiver operating characteristic (ROC) curve analysis, and calibration curves. Subgroup analyses further confirmed that a high CEA/DMAX was associated with poor OS and DFS among patients with stage II colon cancer and among patients with stage II rectal cancer (both P<0.05). CONCLUSIONS: Among patients with stage II CRC, a high CEA/DMAX independently predicted poor OS and DFS, and the predictive abilities were also observed in subgroup analyses of patients with stage II colon cancer or rectal cancer. Furthermore, we developed two nomograms that had good accuracy for predicting the prognosis of stage II CRC.
RESUMO
Purpose: Accumulating evidence indicates that N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) play a crucial role in the occurrence and development of several cancers. We aimed to explore the potential role of m6A-related lncRNA signatures in predicting prognosis for early-stage (stages I and II) colorectal cancer (CRC). Methods: m6A-related lncRNA data were obtained from The Cancer Genome Atlas. Univariate Cox regression analysis was used to screen for prognostic m6A-related lncRNAs. Immune characteristics were analyzed in different subgroups created via unsupervised clustering analysis. Next, patients were randomly divided into training and test cohorts. In the training cohort, least absolute shrinkage and selection operator (LASSO) regression was performed to establish a prognostic model. The predictive value of the signature was evaluated in the training and test cohorts. Drug sensitivity was also examined. Results: A total of 1,478 m6A-related lncRNAs were identified. Two subgroups were created based on the expression of seven prognostic m6A-related lncRNAs. Prognosis was worse for cluster 1 than for cluster 2, and cluster 1 was characterized by increased numbers of M2 macrophages, decreased numbers of memory B cells, and higher expression of checkpoint genes when compared with cluster 2. Five m6A-related lncRNAs were selected to establish a risk prediction signature via LASSO regression. The 3 years overall survival (OS) was higher in the low-risk group than in the high-risk group. The area under the curve at 1, 2, and 3 years was 0.929, 0.954, and 0.841 in the training cohort and 0.664, 0.760, and 0.754 in the test cohort, respectively. Multivariate Cox regression analysis suggests that the risk score was an independent predictor of OS in both the training and test cohorts. A prognostic nomogram based on the five m6A-related lncRNAs and their clinical features was built and verified. The high-risk group was more sensitive to chemotherapeutic drugs (camptothecin and cisplatin) than the low-risk group. Conclusion: We identified two molecular subgroups of early-stage CRC with unique immune features based on seven prognostic m6A-related lncRNAs. Subsequent analyses demonstrated the usefulness of a five m6A-related lncRNA signature as a potential indicator of prognosis in patients with early-stage CRC.