Outcome In Colorectal Cancer Patients Research Articles

Association of preoperative and recurrent serum carcinoembryonic antigen and outcome of colorectal cancer patients with metastatic relapse

BackgroundSeldom have the associations of preoperative CEA (p-CEA) and recurrent CEA (r-CEA) levels as well as changes in p-CEA and r-CEA with survival in patients with stage I–III colorectal cancer (CRC) who have experienced metastatic relapse, been thoroughly examined. Methods241 consecutive patients with stage I–III CRC who experienced metastatic relapse at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and January 2016 were investigated. The influence of p-CEA, r-CEA and CEA alteration on the overall survival (OS) and relapse-to-death survival (RDS) was evaluated. The restricted cubic spline regression model was employed to explore the optimal cut-off value of CEA. ResultsAll 241 patients were categorized into four groups built on their CEA alteration patterns as follows: A, patients presenting elevated p-CEA levels but normal r-CEA levels (P–N); B, patients displaying normal levels of both p-CEA and r-CEA (N–N); C, patients exhibiting elevated levels of both p-CEA and r-CEA (P–P); D, patients with normal p-CEA levels but elevated r-CEA levels (N–P). The correlation between p-CEA and OS (P = 0.3266) and RDS (P = 0.2263) was insignificant. However, r-CEA exhibited a significant association with both OS (P = 0.0005) and RDS (P = 0.0002). Group A demonstrated the longest OS and RDS, whereas group D exhibited the poorest OS and RDS outcomes. For both OS and RDS, the CEA alteration groups served as an independent prognostic indicator. The optimal cut-off threshold for CEA was determined to be 5.1 ng/ml via the restricted cubic spline regression model. Conclusionr-CEA has a stronger correlation with OS and RDS in individuals with stage I–III CRC who have experienced metastatic relapse.The change between p-CEA and r-CEA could further indicate post-relapse survival, thereby facilitating the assessment of mortality risk stratification in stage I-III CRC patients experiencing metastatic relapse.

Abstract 6211: Clinical and prognostic assessment of the lncRNA ZFAS1-related gene signature in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer death with a rapidly rising incidence rate in younger adults. It is projected to be the leading cause of death in adults under 50 years old by 2030. Although progress over the last couple of decades has improved the clinical management of patients affected by CRC, there is a lack of accurate biomarkers to stratify CRC patients. Among several other biomolecules, lncRNAs (long non-coding RNAs) are non-coding transcripts under 200 nucleotides that can regulate gene expression. Furthermore, lncRNAs are important players in oncogenesis and cancer progression and have the potential to be used as reliable biomarkers. Through this study, we explored the clinical relevance of lncRNAs in colorectal cancer. To analyze the distribution of lncRNAs, we utilized de-identified FFPE (formalin-fixed paraffin-embedded) blocks from Augusta University (n = 88). FFPE blocks were sectioned to extract tissue segments and were subsequently stained using H&E (hematoxylin and eosin dyes) to identify the tumor and adjacent normal regions. The quantification of the gene expression was performed using a medium-throughput NanoString platform. Further analyses were performed using clinicopathological features of the institutional cohort and an independent Cancer Genome Atlas (TCGA) dataset. TCGA contains genomic data along with clinical and molecular characterization of over 11,000 samples of various lineages. In the institutional cohort, ZFAS1 showed higher gene expression in the low survival group for stage II and III colorectal cancer patients, while no significant difference was observed in stage I and IV patients. ZFAS1 expression did not significantly correlate with other clinicopathological parameters, including race, alcohol consumption, tobacco consumption, age, grade, and family history of cancer. In an orthogonal TCGA analysis, higher ZFAS1 expression was associated with genomic perturbations, including significantly altered tumor mutational burden (TMB), aneuploidy, fractional genome alteration, and microsatellite instability. Further, a 21-gene signature was developed for prognostication using gene co-expression network analysis. The gene signature was significantly associated with overall and disease-free survival in the TCGA-CRC cohort. Immune deconvolution analysis of the RNA sequencing data revealed that higher expression of the 21-gene signature was associated with increased infiltration of regulatory T cells while being inversely correlated with the overall level of T cells. In conclusion, our study identified the clinicopathological role of ZFAS1 lncRNA and its interaction genes with prognostic significance in colorectal cancer. Further investigation into the therapeutic relevance of the ZFAS1-related gene signature may prove invaluable in improving the clinical outcomes of colorectal cancer patients. Citation Format: Pankaj Kumar Ahluwalia, Tiffanie Leeman, Ashis Mondal, Ashutosh Vashisht, Harmanpreet Singh, Nivin Omar, Kimya Jones, Ravindra Kolhe. Clinical and prognostic assessment of the lncRNA ZFAS1-related gene signature in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6211.

Abstract 866: Identification of survival-associated epithelial cell markers linked to TROP2 through single-cell and bulk sequencing analysis

Abstract Introduction: Colorectal Cancer (CRC) is known for its aggressiveness and drug resistance. This has increased the interest in antibody-drug conjugates (ADCs) as a possible therapy. In this study, we aim to investigate the effects of the ADC target TROP2, on the level of epithelial cells and its correlation with survival outcomes in CRC patients. Methods: Single-cell RNA (scRNA) data was downloaded from Gene Expression Omnibus (GEO) for CRC patients and evaluated for TROP2 expression. Patients were grouped into low and high-TROP2 based on median TROP2 expression, and pseudo-bulk analysis was used to find the differentially expressed genes (DEGs). The DEGs were used to find the survival association in the TCGA-CRC cohort. A risk score was built using principal component analysis (PCA) on the TROP2-DEGs and cutoff point was chosen based on survival. Kaplan-Meier curve was used to compare overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) risk groups. Gene Set Variation Analysis (GSVA) was used to identify the enriched pathways between low- and high-TROP2 in GSE using pseudo-bulk by pooling epithelial cells of individual patients. Results: Of the 10424 cells of 15 different types for 9 CRC patients retrieved from GSE146771, TROP2 was significantly expressed by epithelial cells (n = 766) with mean expression of 1.64 (SD: 1.96, P-value: 0.003) using pseudo-bulk analysis. Three significant DEGs were obtained which are: KIF13B, UCHL3, and PLAC8. These were evaluated for survival association in resectable stages (I-III) CRC patients (n = 419) using PCA to group the patients into low-risk (n = 88) and high-risk (n = 331), using -1.4 as the cutoff point. High risk group showed a better survival with a 1-year survival probability of 94% compared to 90% in the low group and a 5-year survival probability of 74% vs. 46% in the low group. The Kaplan-Meier curve showed that OS, PFS & DFS were significantly better in the low-risk group (p-value = 0.004, 0, 04, and 0.024 respectively). TROP2 and PLAC8 were significantly associated with worse prognosis, whereas UCHL3 was associated with better prognosis (p-value = <0.001), however, KIF3B did not significantly affect the prognosis. APC gene mutation and TP53 were higher in the low-risk group (p-value = 0.004, 0.007 respectively). KRAS-signaling, IL-18-signaling, MET activation of PTK2-signaling were upregulated in high-TROP2 group, while MYC targets, MTORC1 signaling, DNA repair, reactive-oxygen-species signaling, and TCR-signaling were upregulated in low-TROP2. Conclusion: In this study we developed a TROP2-associated risk score that significantly predicted OS, PFS, and DFS in patients with resectable CRC by combining single-cell and bulk-RNA-seq datasets and showing predominant expression of TROP2 in epithelial cells. These findings support the development of TROP2 targeting therapeutics in this space. Citation Format: Noor Nedal Al-Bzour, Ayah Nedal Al-Bzour, Azhar Saeed, Lujia Chen, Anwaar Saeed. Identification of survival-associated epithelial cell markers linked to TROP2 through single-cell and bulk sequencing analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 866.

Abstract 3421: Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer

Abstract Introduction: Dysregulation of the kynurenine pathway of tryptophan metabolism has been linked to the development of inflammation-related chronic diseases, such as colorectal cancer (CRC). Circulating concentrations of certain kynurenine metabolites, the kynurenine/tryptophan ratio (KTR), and the pro-inflammatory marker neopterin increase during inflammation, particularly in response to interferon-gamma. However, comprehensive data on the associations between inflammation markers and kynurenine metabolites and clinical outcomes in CRC patients are lacking. To address this gap in knowledge, we investigated associations of circulating kynurenine metabolites and neopterin with overall survival (OS) in prospectively followed non-metastatic CRC patients. Methods: Pre-surgery blood samples from 2,101 stage I-III CRC patients participating in the international FOCUS consortium were used to measure circulating levels of nine tryptophan-kynurenine pathway metabolites and neopterin using liquid chromatography-tandem mass spectrometry. Multivariable linear regression models and Spearman partial correlation analyses were conducted to quantify associations between kynurenine metabolites and neopterin. Based on the results from correlation analyses, a subset of patients (n=984) was categorized into different groups (‘kynurenine metabolite/neopterin‘: i.e. ‘low/high‘, ‘high/high‘) using the median biomarker concentration as cut-off. Associations of biomarkers with OS were assessed using Cox proportional hazards regression models. All models were adjusted for age at diagnosis, sex, tumor stage, tumor site, circulating creatine levels and cohort. Results: Tryptophan was inversely correlated with neopterin (r=−0.21, β=−0.48, Plinear<0.001). Neopterin was positively correlated with kynurenine (kyn) (r=0.25, β=0.57, Plinear<0.001), the KTR (r=0.42, β=0.87, Plinear<0.001), 3-hydroxykynurenine (r=0.26, β=0.32, Plinear<0.001), anthranilic acid (r=0.29, β=0.36, Plinear<0.001), and quinolinic acid (QA) (r=0.41, β=0.56, Plinear<0.001). After a median follow-up of 3.2 years for OS, 14% (141) patients deceased. While patients with ‘high neopterin’ levels had a 43% increased risk of death (HR, 1.43, 95%CI 0.95-2.16), the ‘high kyn/high neopterin‘ patient group had a 52% increased risk of death (HR, 1.52, 95%CI 1.04-2.22). Similarly, the ‘high QA/high neopterin‘ and ‘high KTR/high neopterin‘ patient groups had a 85% and 89% increased risk of death, respectively (HRQA/Neopt, 1.85, 95%CI 1.24-2.75, HRKTR/Neopt, 1.89, 95%CI 1.27-2.80). Conclusion: Tryptophan-kynurenine pathway activation correlates with inflammation marker neopterin in CRC. Combined associations of kynurenine metabolites and neopterin may be a promising predictor for OS among stage I-III CRC patients. Citation Format: Victoria Damerell, Eline H. van Roekel, Stefanie Brezina, Dieuwertje E. Kok, Tengda Lin, Daniëlle D. Holthuijsen, Jennifer Ose, Caroline Himbert, Simone J. P. Eussen, Arve Ulvik, Fränzel J. van Duijnhoven, Jane C. Figueiredo, Christopher I. Li, Erin M. Siegel, Martin Schneider, David Shibata, Adetunji A. Toriola, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Ellen Kampman, Cornelia M. Ulrich, Biljana Gigic. Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3421.

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

Wnt/β-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased β-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/β-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/β-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of β-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/β-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates β-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced β-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced β-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

In-Hospital Mortality and Associated Factors among Colorectal Cancer Patients in Germany.

In the present study, we used the data from 14 hospitals to systematically evaluate the in-hospital mortality of patients with colorectal cancer as well as its influencing factors in Germany. This multicenter cross-sectional study included hospitalized patients with a main diagnosis of colorectal cancers in the period between January 2019 and July 2023. The outcome of the study was the prevalence of in-hospital mortality. To access the associations between demographic and clinical variables and in-hospital mortality, univariable and multivariable logistic regression analyses were conducted. A total of 4146 colorectal cancer patients (mean age: 70.9 years; 45.3% female) were included. The in-hospital mortality rate was 8.7%. In a multivariable regression, seven variables were significantly associated with an increased in-hospital mortality, including ages of 71-80 years (OR: 2.08; 95% CI: 1.01-4.29), an age group >80 years (OR: 2.44; 95% CI: 1.18-5.05) as compared to an age group ≤ 50 years, patient clinical-complexity level (PCCL) 3 (OR: 3.01 95% CI: 1.81-4.99) and PCCL 4 (OR: 3.76; 95% CI: 2.22-6.38) as compared to PCCL 0, the presence of distant metastases (OR: 4.95; 95% CI: 3.79-6.48), renal failure (OR: 2.38; 95% CI: 1.80-3.14), peritonitis (OR: 1.87; 95% CI: 1.23-2.85), acute posthemorrhagic anemia (OR: 1.55; 95% CI: 1.11-2.15), and respiratory failure (OR: 3.28; 95% CI: 2.44-4.41). Our findings underscore the critical role of renal failure, peritonitis, acute posthemorrhagic anemia, and respiratory failure in influencing the mortality outcomes of colorectal cancer patients during hospitalization. The awareness and management of these risk factors may guide clinicians in formulating targeted interventions to improve patient outcomes and enhance the quality of care for individuals with colorectal cancer.

Circular RNA circNCOA3 promotes tumor progression and anti-PD-1 resistance in colorectal cancer.

Aim: Circular RNAs (circRNAs) have been found to be involved in tumor progression, but their role in colorectal cancer (CRC) immune escape remains to be elucidated. Methods: circRNAs differentially expressed in responsive and resistant CRC tissues to programmed cell death 1 (PD-1) antibody therapy were identified by microarray analysis. The clinical and pathological significance of circNCOA3 was validated in a separate cohort of CRC samples. The function of circNCOA3 was explored experimentally. RNA immunoprecipitation and luciferase activity assays were conducted to identify downstream targets of circNCOA3. Results: The circNCOA3 was markedly overexpressed in CRC samples resistant to PD-1 blockade. circNCOA3 expression was significantly correlated with adverse tumor phenotypes and poor outcomes in CRC patients. Knockdown of circNCOA3 expression markedly suppressed the proliferative and invasive capability of CRC cells. Moreover, knockdown of circNCOA3 increased the proportion of CD8+ T cells while decreasing the proportion of myeloid-derived suppressor cells (MDSCs). Knockdown of circNCOA3 inhibited tumor growth and increased the sensitivity to PD-1 antibody treatment in mouse tumor models. Further studies revealed that circNCOA3 acted as a competing endogenous RNA (ceRNA) for miR-203a-3p.1 to influence the level of CXCL1. Conclusion: Our findings indicate that circNCOA3 might be useful as a potential biomarker to predict the efficacy and prognosis of CRC patients treated with anti-PD-1 therapy.

Achieving Textbook Outcomes in Colorectal Cancer Surgery Is Associated with Improved Long-Term Survival: Results of the Multicenter Prospective Cohort Study.

Background: The outcomes of patients with colorectal cancer greatly depend on the quality of their surgical care. However, relying solely on a single quality indicator does not adequately capture the multifaceted nature of modern perioperative care. A new tool-"Textbook Outcome" (TO)-has been suggested to provide a comprehensive evaluation of surgical quality. This study aims to examine how TO affects the long-term outcomes of colorectal cancer patients who are scheduled for surgery. Methods: The data of all patients undergoing elective colorectal cancer resection with primary anastomosis at two major cancer treatment centers in Lithuania-Vilnius University Hospital Santaros Klinikos and National Cancer Institute-between 2014 and 2018 were entered into the prospectively maintained database. The study defined TO as a composite quality indicator that incorporated seven parameters: R0 resection, retrieval of ≥12 lymph nodes, absence of postoperative complications during the intrahospital period, hospital stay duration of fewer than 14 days, no readmission within 90 days after surgery, no reinterventions within 30 days after surgery, and no 30-day mortality. Long-term outcomes between patients who achieved TO and those who did not were compared. Factors associated with failure to achieve TO were identified. Results: Of the 1524 patients included in the study, TO was achieved by 795 (52.2%). Patients with a higher ASA score (III-IV) were identified to have higher odds of failure to achieve TO (OR 1.497, 95% CI 1.203-1.863), while those who underwent minimally invasive surgery had lower odds for similar failure (OR 0.570, 95% CI 0.460-0.706). TO resulted in improved 5-year overall-(80.2% vs. 65.5%, p = 0.001) and disease-free survival (76.6% vs. 62.6%; p = 0.001) rates. Conclusions: Elective colorectal resections result in successful TO for 52.5% of patients. The likelihood of failure to achieve TO is increased in patients with a high ASA score, while minimally invasive surgery is associated with higher TO rates. Patients who fail to achieve successful surgical outcomes experience reduced long-term outcomes.

Delineating the role of nuclear receptors in colorectal cancer, a focused review.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer.

Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single-cell RNA sequencing (scRNA-seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor-associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF-1α destabilization, leading to reduction in M2-like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN-response genes. Expression of these genes contributed to anti-tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT-initiated TAM-specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

Cancer-Related Fatigue and Its Influencing Factors Among Colorectal Cancer Patients: A Generalized Linear Modeling Approach.

This study aimed to improve cancer-related fatigue (CRF) and health outcomes of colorectal cancer patients by understanding the status quo of CRF, exploring the relations of coping, anxiety symptoms, depressive symptoms, body image perception and CRF, and also identifying the factors affecting CRF based on a generalized linear modeling approach. An exploratory cross-sectional study was conducted on 370 colorectal cancer patients at two hospitals in Anhui Province, China, from July 2020 to February 2021. The data were collected by using general information questionnaire, cancer fatigue scale, simplified coping style questionnaire, generalized anxiety disorder-7 scale, patient health questionnaire-9, and body image scale. Descriptive statistics, t-tests, one-way analysis of variance, Pearson correlation analyses, and generalized linear model analyses were applied to analyze the data. The average CRF score of the patients was 21.612 (SD=6.160), with a prevalence rate of 69.4% for clinically relevant fatigue. The generalized linear model revealed that: In step 1, gender (female) (B=1.799, Waldχ2=7.506, p=0.006), per capita monthly income (1001-3000 RMB) (B=-1.673, Waldχ2=5.536, p=0.019) and treatment modalities (chemotherapy+others) (B=2.425, Waldχ2=8.211, p=0.004) were related to CRF. In step 2, depressive symptoms (B=1.223, Waldχ2=129.019, p<0.001) and negative coping strategies (B=0.215, Waldχ2=11.347, p=0.001) exhibited significant positive correlations with CRF, positive coping strategies (B=-0.319, Waldχ2=59.175, p<0.001) showed significant negative correlations with CRF; While anxiety symptoms (B=0.162, Waldχ2=1.840, p=0.175) and body image perception (B=0.013, Waldχ2=0.048, p=0.826) had no correlations with CRF. The prevalence of CRF was relatively high among colorectal cancer patients. Coping and depressive symptoms were the modifiable influencing factors of CRF. Tailored interventions dedicated to promoting positive coping behavior, diminishing negative coping behavior and reducing depressive symptoms may improve the CRF of patients with colorectal cancer. Healthcare providers working with these patients should receive corresponding education and training in these complementary treatments. Additionally, when developing non-pharmacological interventions, appropriate consideration of the patients' gender, income condition and the type of anticancer treatment is also necessary.

Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer

BackgroundColorectal cancer (CRC), is the third most prevalent cancer across the globe, and is often detected at advanced stage. Late diagnosis of CRC, leave the chemotherapy and radiotherapy as the main options for the possible treatment of the disease which are associated with severe side effects. In the present study, we seek to explore CRC gene expression data using a systems biology framework to identify potential biomarkers and therapeutic targets for earlier diagnosis and treatment of the disease. MethodsThe expression data was retrieved from the gene expression omnibus (GEO). Differential gene expression analysis was conducted using R/Bioconductor package. The PPI network was reconstructed by the STRING. Cystoscope and Gephi software packages were used for visualization and centrality analysis of the PPI network. Clustering analysis of the PPI network was carried out using k-mean algorithm. Gene-set enrichment based on Gene Ontology (GO) and KEGG pathway databases was carried out to identify the biological functions and pathways associated with gene groups. Prognostic value of the selected identified hub genes was examined by survival analysis, using GEPIA. ResultsA total of 848 differentially expressed genes were identified. Centrality analysis of the PPI network resulted in identification of 99 hubs genes. Clustering analysis dissected the PPI network into seven interactive modules. While several DEGs and the central genes in each module have already reported to contribute to CRC progression, survival analysis confirmed high expression of central genes, CCNA2, CD44, and ACAN contribute to poor prognosis of CRC patients. In addition, high expression of TUBA8, AMPD3, TRPC1, ARHGAP6, JPH3, DYRK1A and ACTA1 was found to associate with decreased survival rate. ConclusionOur results identified several genes with high centrality in PPI network that contribute to progression of CRC. The fact that several of the identified genes have already been reported to be relevant to diagnosis and treatment of CRC, other highlighted genes with limited literature information may hold potential to be explored in the context of CRC biomarker and drug target discovery.

Short-term outcomes after laparoscopic colorectal cancer surgery in patients over 90 years old: a Japanese multicenter study.

The effect of laparoscopic surgery on short-term outcomes in colorectal cancer patients over 90 years old has remained unclear. We reviewed 87 colorectal cancer patients aged over 90 years who underwent surgery between 2016 and 2022. Patients were divided into an open surgery group (n = 22) and a laparoscopic surgery group (n = 65). The aim of this study was to investigate the effect of laparoscopic surgery on postoperative outcome in elderly colorectal cancer patients, as compared to open surgery. Seventy-eight patients (89.7%) had comorbidities. Frequency of advanced T stage was lower with laparoscopic surgery (p = 0.021). Operation time was longer (open surgery 146min vs. laparoscopic surgery 203min; p = 0.002) and blood loss was less (105 mL vs. 20 mL, respectively; p < 0.001) with laparoscopic surgery. Length of hospitalization was longer with open surgery (22 days vs. 18 days, respectively; p = 0.007). Frequency of infectious complications was lower with laparoscopic surgery (18.5%) than with open surgery (45.5%; p = 0.021). Multivariate analysis revealed open surgery (p = 0.026; odds ratio, 3.535; 95% confidence interval, 1.159-10.781) as an independent predictor of postoperative infectious complications. Laparoscopic colorectal resection for patients over 90 years old is a useful procedure that reduces postoperative infectious complications.

Resveratrol restrains colorectal cancer metastasis by regulating miR-125b-5p/TRAF6 signaling axis.

Colorectal cancer is one of the most common malignancies with a high incidence, metastatic tendency and low 5-year survival rate. Resveratrol, a polyphenolic compound has been shown to inhibit colorectal cancer metastasis in recent studies. Its underlying molecular mechanism remains to be elucidated. Our findings demonstrated that miR-125b-5p, acting as a tumor suppressor, was conspicuously down-regulated in both colorectal cancer tissues and cell lines. The expression of miR-125b-5p negatively correlated with the expression of its direct target TNF receptor associated factor 6 (TRAF6). Both miR-125b-5p overexpression and TRAF6 knockdown inhibited metastasis of colorectal cancer cells. In addition, we uncovered that resveratrol up-regulated miR-125b-5p by increasing its stability and suppressed TRAF6-induced signal pathway in a dose/time-dependent manner. Resveratrol could significantly curtail the migration and invasion of colorectal cancer cells, which was counteracted by miR-125b-5p knockdown or TRAF6 overexpression. These results indicated that resveratrol could restrain colorectal cancer metastasis by promoting miR-125b-5p/TRAF6 signaling axis. Furthermore, lung metastasis models of colorectal cancer were constructed by tail vein injection. Down-regulation of miR-125b-5p could facilitate colorectal cancer metastasis in vivo, which could be impeded by resveratrol. In conclusion, our findings delineated the miR-125b-5p/TRAF6 signaling axis as a novel molecular mechanism underlying the metastatic process in colorectal cancer, as well as a prospective therapeutic target. Resveratrol disrupts colorectal cancer metastasis by activating miR-125b-5p/TRAF6 signal pathway and might improve the clinical outcome of colorectal cancer patients with low expression of miR-125b-5p.

Construction of an immune gene expression meta signature to assess the prognostic risk of colorectal cancer patients.

Despite recent advancements in colorectal cancer (CRC) treatment, particularly with the introduction of immunotherapy and checkpoint inhibitors, the efficacy of these therapies remains limited to a subset of patients. To address this challenge, our study aimed to develop a prognostic biomarker based on immune-related genes to predict better outcomes in CRC patients and aid in treatment decision-making. We comprehensively analysed immune gene expression signatures associated with CRC prognosis to construct an immune meta-signature with prognostic potential. Utilising data from The Cancer Genome Atlas (TCGA), we employed Cox regression to identify immune-related genes with prognostic significance from multiple studies. Subsequently, we compared the expression levels of immune genes, levels of immune cell infiltration, and various immune-related molecules between high-risk and low-risk patient groups. Functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses provided insights into the biological pathways associated with the identified prognostic genes. Finally, we validated our findings using a separate CRC cohort from the Gene Expression Omnibus (GEO). Integration of the prognostic genes revealed significant disparities in survival outcomes. Differential expression analysis identified a set of immune-associated genes, which were further refined using LASSO penalisation and Cox regression. Univariate Cox regression analyses confirmed the autonomy of the gene signature as a prognostic indicator for CRC patient survival. Our risk prediction model effectively stratified CRC patients based on their prognosis, with the high-risk group showing enrichment in pro-oncogenic terms and pathways. Immune infiltration analysis revealed an augmented presence of certain immunosuppressive subsets in the high-risk group. Finally, we validated the performance of our prognostic model by applying the risk score equation to a different CRC patient dataset, confirming its prognostic potential in this new cohort. Overall, our study presents a novel immune-related gene signature with promising implications for predicting cancer progression and prognosis, thereby enabling more personalised management strategies for CRC patients.

Barriers and Facilitators Related to Undertaking Physical Activities in Colorectal Cancer Patients: A Scoping Review.

Colorectal cancer (CRC) and its treatments cause significant acute, chronic, or latent adverse effects, leading to decreased physical function and quality of life. Robust evidence supports the positive effects of physical activity (PA) on various health outcomes in CRC patients. However, there is limited understanding regarding the factors that influence PA engagement, including facilitators, preferences, and barriers in this population. This scoping review aims to document the breadth and depth of literature concerning the various aspects of PA participation among patients with CRC. We conducted a scoping review of PA among CRC patients. We searched several databases, including PubMed, Web of Science, Embase, and Cochrane, from their inception to 25 July 2023. Multiple reviewers were involved in all screening and data abstractions. The search yielded 834 individual citations after removing duplicates. After screening the titles and abstracts, 20 articles underwent full-text review, and 11 were included. Our research findings indicate that among CRC patients, the most prevalent facilitators/preferences for PA are understanding its importance and perceiving its benefits, whereas treatment-related effects and lack of time are the most common barriers. CRC patients have unique facilitators and barriers concerning PA. Further research and clinical interventions are required to support and encourage this population to participate in and maintain regular PA.

Comprehensive analysis of the Cullin family of genes reveals that CUL7 and CUL9 are the significant prognostic biomarkers in colorectal cancer.

The purpose of this study is to decipher the role of Cullin family genes in colorectal cancer (CRC), drawing insights from comprehensive analyses encompassing multiple databases and experimental validations. UALCAN, GEPIA2, Human Protein Atlas (HPA), KM plotter, cBioPortal, TISIDB, DAVID, colon cancer cell lines culturing, gene knockdown, CCK8 assay, colony formation, and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) assays. Initial scrutiny of The Cancer Genome Atlas (TCGA) CRC datasets through the UALCAN and GEPIA databases unveiled significant alterations in Cullin family gene expressions. Elevations in CUL1, CUL2, CUL4A, CUL4B, CUL5, CUL7, and CUL9 were observed in CRC tissues compared to normal counterparts, while CUL3 demonstrated down-regulation consistently across datasets. Further exploration revealed notable correlations between Cullin gene expressions and various clinical parameters of CRC patients, substantiating the potential diagnostic and prognostic utility of these genes. Protein expression analyses conducted via the HPA corroborated the transcriptomic findings, indicating high levels of Cullin proteins in CRC tissues. Prognostic assessments identified CUL7 and CUL9 as significant predictors of poor survival outcomes in CRC patients, emphasizing their clinical relevance. Genetic alterations within the Cullin family genes were elucidated through the cBioPortal database, shedding light on the mutation landscape and prevalence of missense mutations in CRC. Immune subtype and tumor immune microenvironment analyses underscored the intricate interplay between Cullin family genes and immune processes in CRC. Experimental validation in CRC cell lines demonstrated the functional significance of CUL7 and CUL9 in promoting CRC growth, further solidifying their roles as potential therapeutic targets. Overall, these multifaceted analyses elucidated the intricate involvement of Cullin family genes in CRC pathogenesis and provided valuable insights for future diagnostic and therapeutic endeavors in CRC management.

Beta-Hydroxybutyrate Augments Oxaliplatin-Induced Cytotoxicity by Altering Energy Metabolism in Colorectal Cancer Organoids.

Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients.

Abstract C075: Socioeconomic status and genetic ancestry correlate with differences in clinical outcomes for colorectal cancer patients treated at a single tertiary cancer center

Abstract Intro: Lower socioeconomic status (SES) and African ancestry have been linked to poor overall survival (OS) in colorectal cancer (CRC). To better understand the interplay between these variables, we analyzed clinical and genomic real-world data from a large cohort of patients treated at a single tertiary center. Methods: Clinical annotations including sex, primary tumor location, age and stage at diagnosis were extracted from the electronic health record for 3,817 CRC patients who underwent clinical genomic sequencing at Memorial Sloan Kettering Cancer Center between 2014 and 2022. We also cataloged each patient’s type of primary health insurance (commercial, Medicare, Medicaid or self-pay). Socioeconomic status was assessed from each patient’s billing address using the Yost index (YI), which is a location-dependent percentile score based on household incomes, house values, rent, poverty, education, and employment statistics. Genetic ancestry was determined from DNA sequencing data using reference populations from the 1000 Genomes project, including European (EUR), African (AFR), East Asian (EAS), and Southeast Asian (SAS). Specific ancestries were assigned based on an ancestral fraction of &amp;gt;80%, otherwise patients were labeled as admixed (ADM). OS was measured from time of diagnosis to last follow-up. Results: Our cohort included 2,627 EUR, 195 EAS, 206 AFR, 61 SAS and 728 ADM patients. The median YI within our cohort was 18 [IQR: 30]. No significant associations were observed between YI and primary tumor location, age or stage at diagnosis. We observed significant differences in YI based on type of health insurance (median 15 for commercial vs. 29 for Medicaid, p&amp;lt;0.0001) and sex (median 15 in males vs. 17 in females, p=0.0113). YI was also strongly associated with genetic ancestry, with AFR patients exhibiting significantly higher YI values than other ancestries (median 45.5 vs. 14, p&amp;lt;0.0001). No significant differences in YI were observed among EUR, EAS and SAS patients. When all ancestries were analyzed together, patients within the bottom YI quartile (most affluent) had significantly longer OS than patients from the top YI quartile (most deprived) (median 52.3 vs. 61.6 months, p=0.023). No differences in OS were observed between EUR, EAS and SAS patients, but patients of AFR ancestry had significantly shorter OS than the rest (median 44.5 vs. 56.5 months, p= 0.016). When the analysis was restricted to patients of EUR, EAS and SAS ancestry, OS was still significantly shorter for patients within the top vs. bottom YI quartile (median 52.6 vs. 64.4 months, p=0.011). Conclusions: Patients of African ancestry exhibited lower socioeconomic status and shorter survival. Even when the analysis was restricted to other genetic ancestries, patients with the lowest socioeconomic status still had poorer clinical outcomes. The existence of these differences within a relatively homogeneous cohort of patients treated at the same institution highlights the need to better understand and address health disparities in CRC. Citation Format: Tejiri Agbamu, Xuechun Bai, Henry Walch, Michele Waters, Anisha Luthra, Kanika Arora, Christopher Fong, Doori Rose, Hannah Williams, Michael Berger, Karuna Ganesh, Julio Garcia-Aguilar, Nikolaus Schultz, Rona Yaegar, Walid Chatila, Francisco Sanchez-Vega. Socioeconomic status and genetic ancestry correlate with differences in clinical outcomes for colorectal cancer patients treated at a single tertiary cancer center [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C075.

Abstract C077: Effects of treatment delays on colorectal cancer survival

Abstract Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Understanding the influence of patient characteristics and treatment modalities on delays in care and related outcomes is crucial for optimizing treatment strategies and improving patient survival. Methods: A retrospective analysis of 2,359 CRC patients from the PLCO trial was conducted to assess the relationships between treatment initiation delays and survival outcomes. Descriptive statistics, Spearman's correlation coefficients, and Cox proportional hazards regression analyses were employed to analyze the data. Results: Among other factors, patients with disabilities and those using ibuprofen exhibited a higher hazard ratio and a lower hazard ratio, respectively, indicating the influence of these factors on patient outcomes. Despite examining multiple waiting time predictors, no significant associations were found between these predictors and mortality risk. The model's non-significant likelihood ratio chi-square and log-likelihood value suggested that it did not provide an adequate fit to the data. Discussion: This study highlights the importance of understanding the relationships between patient characteristics, treatment modalities, and their impact on patient outcomes in CRC patients. While curative resection was significantly associated with improved survival, neoadjuvant chemotherapy did not demonstrate a significant effect on mortality. The lack of association between waiting time predictors and mortality risk suggests the need to explore additional factors influencing patient outcomes. Conclusion: In conclusion, the study provides valuable insights into the relationships between patient characteristics, treatment modalities, and their impact on patient outcomes in CRC patients. Further research is needed to identify additional factors that may influence mortality risk and to optimize treatment strategies for this patient population. Citation Format: Percy Guzman Montero. Effects of treatment delays on colorectal cancer survival [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C077.