Prognostic Marker In Colon Cancer Research Articles

Diet and epigenetics of colon carcinogenesis: A review article

The following article includes a chart illustrating the dietary components of various food classes that are involved in the pathogenesis of colorectal cancer (CRC), as well as information on the key players in the digestive tract microbiota and the many dysfunctions involved in the onset or progression of CRC. With its complex course throughout history, colorectal cancer has advanced the understanding of its initiation and improvement. The understanding of how colorectal cancer starts and improves through eating less has advanced over time. By and enormous, the utilization of ruddy and organized meats has been related to an expanded chance of start. These meats contain compounds such as nitrates and nitrites that can serve as diagram carcinogens inside the colon. Understanding how diets affect epigenetic modifications inside the intestinal mucosa is particularly important since abnormally methylated genes may serve as early detection and prognostic markers for colon cancer. Epigenetic changes, such as changes in methylation, are potentially reversible and, therefore, offer interesting targets for supportive and preventative therapy, unlike intrinsic changes in cancer. The growing role of microbial metabolites and a few clearly beneficial dietary additions in the management of CRC are outlined in this article.

Prognostic value of translationally controlled tumor protein in colon cancer.

The translationally controlled tumor protein (TCTP) is a highly conserved protein involved in a variety of normal cell functions and disease processes. Preclinical studies revealed that TCTP has anti-apoptotic properties, promotes cell growth and division and is involved in cancer progression by promoting invasion and metastasis. The present study explored the potential value of TCTP as a prognostic marker in colon cancer. A retrospective analysis of 74 patients with colon cancer was performed. Using immunohistochemistry, TCTP levels in the primary tumor were assessed semi-quantitatively by the calculation of cytoplasmic and nuclear H-score. Cytoplasmic TCTP levels in the primary tumor had no statistically significant association with disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) in the present patient population. Patients whose primary tumors had a negative nuclear TCTP expression had significantly improved clinical outcomes. The PFS for the negative nuclear TCTP expression group was 7.7 months [95% confidence interval (CI), 5.8-9.5] compared with 5.5 months (95% CI, 3.2-7.8) in the group with positive nuclear expression (P=0.023, Mantel-Cox log-rank). Patients with a negative nuclear expression of TCTP had a significantly higher median OS (22.2 months; 95% CI, 16.1-28.3) compared with those with positive TCTP nuclear expression (median 13.2 months; 95% CI, 10.1-16.3; P=0.008, Mantel-Cox log-rank). In a multivariate Cox regression model, a positive nuclear TCTP H-score was an independent risk factor for worse PFS and OS. The 1-year OS rate in the group with negative nuclear TCTP expression was 86.3% compared with 56.5% in patients with positive nuclear TCTP expression (P=0.008). The present study suggested that semiquantitative H-score measurement of TCTP levels in the nuclei of tumor cells from the primary tumor is a potential prognostic marker for clinical outcomes in patients with colon cancer.

Prognostic histological markers in colorectal cancer

Colon carcinomas are among the most common malignant tumors worldwide. The critical evaluation of different therapy options is particularly relevant. On the one hand, colon carcinomas more often occur at an older age, on the other hand patients with colon carcinomas often live for decades after initial diagnosis - it is just as important to avoid overtreatment as it is to avoid undertreatment, which shortens the patient's life span. Prognostically effective biomarkers are decision-making tools. There are clinical, molecular, and histological prognostic markers-the latter are presented in this paper. To present the current state of knowledge on morphologically determinable prognostic markers in colon cancer. Literature search in PubMed and Medline. In their daily work, pathologists identify highly relevant prognostic markers that are essential for therapeutic decisions. These markers must be communicated to the clinical colleague. The most important and longest-known prognostic markers are staging (TNM), including local resection status, lymph node involvement and number on the surgical specimen, vascular invasion, perineural sheath infiltration, and histomorphologic growth pattern determination (e.g., micropapillary colon carcinoma is associated with avery unfavorable prognosis). Recently, tumor budding has been added, which has practical applications especially in endoscopically applied pT1 carcinomas ("malignant polyps").

Abstract 165: Characterizing CLK3 in the colonic epithelium

Abstract The purpose of this study is to determine the function of CLK3 in the colonic epithelium and colon cancer. The intestinal epithelium undergoes constant renewal and is tightly regulated. Disruption of its homeostasis can result in the development of colorectal cancer (CRC). Glycogen synthase kinase 3 (GSK3) is a kinase that plays a central role in multiple signaling pathways including cellular proliferation. Our lab previously performed an siRNA screen to investigate hundreds of kinases to identify candidates which could interact with GSK3. Among the over 500 kinases that were tested, a protein kinase called CDC-like kinase 3 (CLK3) was identified as the strongest interaction with GSK3. We found that inhibition of GSK3 and CLK3 synergized to kill cancer cells. This led us to focus on CLK3 as a potential therapeutic target kinase in colon cancer. CLK3 is part of a four-member family of CDC-like kinases involved in pre-mRNA splicing. They are dual-specificity kinases, meaning they can target both tyrosine and serine/threonine substrates. CLK3 is also a poor prognostic marker in colon cancer, with high expression of CLK3 leading to poor outcome of disease. In human colonic epithelial cells, we show that loss of CLK3 dampens Wnt response. This data, along with the strong genetic interaction with GSK3, suggests a role of CLK3 in the Wnt pathway. Because Wnt signaling is higher in the stem cell region of the crypt, and CLK3 shows a role in Wnt activity in human colonic epithelial cells, we hypothesize that CLK3 regulates mRNA splicing to promote Wnt signaling and stemness in colonic progenitor cells and carcinogenesis. We are currently performing transcriptomics and phosphoproteomics in CLK3 CRISPR knockout cells to identify an mRNA-splicing and phosphorylation signature. We have found that the induction of Wnt-related pathway genes are lost in CLK3 knockout cells. Additionally, we are categorizing CLK3-dependent pre-mRNAs splicing events into functional groups controlling cell fate and validating in patient-derived normal and tumor organoid models. This work highlights CLK3 as a critical regulator of gut stem cells and potentially colorectal cancer stem cells. Citation Format: Carly Cabel, Curtis Thorne. Characterizing CLK3 in the colonic epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 165.

Identification and validation of a seven-gene prognostic marker in colon cancer based on single-cell transcriptome analysis.

Colon cancer (CC) is one of the most commonly diagnosed tumours worldwide. Single‐cell RNA sequencing (scRNA‐seq) can accurately reflect the heterogeneity within and between tumour cells and identify important genes associated with cancer development and growth. In this study, scRNA‐seq was used to identify reliable prognostic biomarkers in CC. ScRNA‐seq data of CC before and after 5‐fluorouracil treatment were first downloaded from the Gene Expression Omnibus database. The data were pre‐processed, and dimensionality reduction was performed using principal component analysis and t‐distributed stochastic neighbour embedding algorithms. Additionally, the transcriptome data, somatic variant data, and clinical reports of patients with CC were obtained from The Cancer Genome Atlas database. Seven key genes were identified using Cox regression analysis and the least absolute shrinkage and selection operator method to establish signatures associated with CC prognoses. The identified signatures were validated on independent datasets, and somatic mutations and potential oncogenic pathways were further explored. Based on these features, gene signatures, and other clinical variables, a more effective predictive model nomogram for patients with CC was constructed, and a decision curve analysis was performed to assess the utility of the nomogram. A prognostic signature consisting of seven prognostic‐related genes, including CAV2, EREG, NGFRAP1, WBSCR22, SPINT2, CCDC28A, and BCL10, was constructed and validated. The proficiency and credibility of the signature were verified in both internal and external datasets, and the results showed that the seven‐gene signature could effectively predict the prognosis of patients with CC under various clinical conditions. A nomogram was then constructed based on features such as the RiskScore, patients' age, neoplasm stage, and tumor (T), nodes (N), and metastases (M) classification, and the nomogram had good clinical utility. Higher RiskScores were associated with a higher tumour mutational burden, which was confirmed to be a prognostic risk factor. Gene set enrichment analysis showed that high‐score groups were enriched in ‘cytoplasmic DNA sensing’, ‘Extracellular matrix receptor interactions’, and ‘focal adhesion’, and low‐score groups were enriched in ‘natural killer cell‐mediated cytotoxicity’, and ‘T‐cell receptor signalling pathways’, among other pathways. A robust seven‐gene marker for CC was identified based on scRNA‐seq data and was validated in multiple independent cohort studies. These findings provide a new potential marker to predict the prognosis of patients with CC.

388MO Tumor budding, an important prognostic factor in stage III colon cancer patients treated with oxaliplatin-based chemotherapy

Histological growth characteristics at the invasive front may reflect tumor aggressiveness. Specifically, tumor budding (TB), defined as single cancer cells or cluster comprising less than five cells and representing the dynamic process of epithelial-mesenchymal transition, is listed among prognostic markers in colon cancer (CC). However, its use for a better disease stratification needs to be further explored. Its prognostic role was thus evaluated in a phase III trial investigating 3 vs 6 months of oxaliplatin-based adjuvant treatment in stage III CC patients.

Identification of Distinct Molecular Patterns and a Four-Gene Signature in Colon Cancer Based on Invasion-Related Genes.

BackgroundThe pathological stage of colon cancer cannot accurately predict recurrence, and to date, no gene expression characteristics have been demonstrated to be reliable for prognostic stratification in clinical practice, perhaps because colon cancer is a heterogeneous disease. The purpose was to establish a comprehensive molecular classification and prognostic marker for colon cancer based on invasion-related expression profiling.MethodsFrom the Gene Expression Omnibus (GEO) database, we collected two microarray datasets of colon cancer samples, and another dataset was obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) further underwent univariate analysis, least absolute shrinkage, selection operator (LASSO) regression analysis, and multivariate Cox survival analysis to screen prognosis-associated feature genes, which were further verified with test datasets.ResultsTwo molecular subtypes (C1 and C2) were identified based on invasion-related genes in the colon cancer samples in TCGA training dataset, and C2 had a good prognosis. Moreover, C1 was more sensitive to immunotherapy. A total of 1,514 invasion-related genes, specifically 124 downregulated genes and 1,390 upregulated genes in C1 and C2, were identified as DEGs. A four-gene prognostic signature was identified and validated, and colon cancer patients were stratified into a high-risk group and a low-risk group. Multivariate regression analyses and a nomogram indicated that the four-gene signature developed in this study was an independent predictive factor and had a relatively good predictive capability when adjusting for other clinical factors.ConclusionThis research provided novel insights into the mechanisms underlying invasion and offered a novel biomarker of a poor prognosis in colon cancer patients.

PROGNOSTIC ROLE OF MOLECULAR SUBTYPES OF COLON CANCER. A CURRENT VIEW ON THE PROBLEM

Purpose of the study: to review the available data on the heterogeneity of colon cancer and to assess the prognostic significance of colon cancer subtypes.Material and Methods. Medline, PubMed, Cochrane library, elibrary databases were used to identify studies that characterized the current view on the problem of choosing the optimal postoperative treatment for colon cancer.Results. the review showed the results of international studies of colon cancer subtypes based on complex multomics characteristics. Particular attention was paid to the description of modern studies on the search for prognostic markers for colon cancer. The relevance of the study of immunohistochemical markers was confirmed by the analysis of the world literature. the outcomes will make it possible to classify colon cancer into molecular subtypes in real clinical practice and, as a consequence, significantly improve the effectiveness of adjuvant therapy.

A Prognostic Model for Colon Cancer Patients Based on Eight Signature Autophagy Genes.

ObjectiveTo screen key autophagy genes in colon cancer and construct an autophagy gene model to predict the prognosis of patients with colon cancer.MethodsThe colon cancer data from the TCGA were downloaded as the training set, data chip of GSE17536 as the validation set. The differential genes of the training set were obtained and were analyzed for enrichment and protein network. Acquire autophagy genes from Human Autophagy Database www.autophagy.lu/project.html. Autophagy genes in differentially expressed genes were extracted using R-packages limma. Using LASSO/Cox regression analysis combined with clinical information to construct the autophagy gene risk scoring model and divide the samples into high and low risk groups according to the risk value. The Nomogram assessment model was used to predict patient outcomes. CIBERSORT was used to calculate the infiltration of immune cells in the samples and study the relationship between high and low risk groups and immune checkpoints.ResultsNine hundred seventy-six differentially expressed genes were screened from training set, including five hundred sixty-eight up-regulated genes and four hundred eight down regulated genes. These differentially expressed genes were mainly involved: the regulation of membrane potential, neuroactive ligand-receptor interaction. We identified eight autophagy genes CTSD, ULK3, CDKN2A, NRG1, ATG4B, ULK1, DAPK1, and SERPINA1 as key prognostic genes and constructed the model after extracting the differential autophagy genes in the training set. Survival analysis showed significant differences in sample survival time after grouping according to the model. Nomogram assessment showed that the model had high reliability for predicting the survival of patients with colon cancer in the 1, 3, 5 years. In the high-risk group, the infiltration degrees of nine types of immune cells are different and the samples can be well distinguished according to these nine types of immune cells. Immunological checkpoint correlation results showed that the expression levels of CTLA4, IDO1, LAG3, PDL1, and TIGIT increased in high-risk groups.ConclusionThe prognosis prediction model based on autophagy gene has a good evaluation effect on the prognosis of colon cancer patients. Eight key autophagy genes can be used as prognostic markers for colon cancer.

Angiogenesis is promoted by exosomal DPP4 derived from 5-fluorouracil-resistant colon cancer cells

Cancer cells can communicate with the tumor microenvironment and contribute to tumor progression. However, the effects of drug-resistant tumor cells on angiogenesis are unclear. Current anti-angiogenic strategies also have limitations and it would be useful to develop novel targets and treatment strategies. Here, our study showed that the conditioned medium and exosomes from 5-FU-resistant colon cancer cells promoted angiogenesis, and we observed that exosomal dipeptidyl peptidase IV (DPP4) was a potent inducer of this angiogenesis. DPP4-enriched exosomes increased periostin (POSTN) expression in human umbilical vein endothelial cells via Twist1 nuclear translocation or activating Smad signaling pathway, while silencing or inhibition of DPP4 neutralized those effects. The in vivo and clinical data indicated that high DPP4 expression was related to tumor progression. These findings indicate that DPP4 may be a target for inhibiting angiogenesis in 5-FU-resistant colon cancer. Furthermore, exosomal DPP4 concentrations may be a useful prognostic marker for colon cancer.

Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer.

Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance. Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene. We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013). We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.

Expression and significance of miR-654-5p and miR-376b-3p in patients with colon cancer.

BACKGROUNDThe relationship between microRNAs, such as miR-654-5p and miR-376b-3p, and the prognosis of colon cancer has not been studied until now.AIMTo evaluate the expression levels of miR-654-5p and miR-376b-3p and their clinical significance in colon cancer.METHODSRT-qPCR was performed to evaluate miR-654-5p and miR-376b-3p expression in 34 pairs of colon cancer and adjacent noncancerous tissues. Subsequently, the association of miR-654-5p and miR-376b-3p expression with clinical factors or the survival of patients suffering from colon cancer was determined by using The Cancer Genome Atlas.RESULTSmiR-654-5p was upregulated and miR-376b-3p was downregulated in colon cancer tissues compared with adjacent noncancerous tissues (P < 0.001). Increased miR-654-5p and decreased miR-376b-3p expression levels were significantly associated with metastasis and clinical stage. Moreover, a univariate analysis demonstrated that colon cancer patients with high miR-654-5p or low miR-376b-3p expression (P = 0.044 and 0.007, respectively) had a poor overall survival rate. A multivariate analysis identified high miR-654-5p expression and low miR-376b-3p expression as independent predictors of poor survival in colon cancer patients.CONCLUSIONUpregulated miR-654-5p and downregulated miR-376b-3p may be associated with tumour progression in colon cancer, and these microRNAs may serve as independent prognostic markers for colon cancer.

L1TD1 - a prognostic marker for colon cancer

BackgroundPrognostic markers specific to a particular cancer type can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities.MethodsGene expression data was analyzed from three independent colon cancer microarray gene expression data sets (N = 1052). Survival analysis was performed for the three data sets, stratified by the expression level of the LINE-1 type transposase domain containing 1 (L1TD1). Correlation analysis was performed to investigate the role of the interactome of L1TD1 in colon cancer patients.ResultsWe found L1TD1 as a novel positive prognostic marker for colon cancer. Increased expression of L1TD1 associated with longer disease-free survival in all the three data sets. Our results were in contrast to a previous study on medulloblastoma, where high expression of L1TD1 was linked with poor prognosis. Notably, in medulloblastoma L1TD1 was co-expressed with its interaction partners, whereas our analysis revealed lack of co-expression of L1TD1 with its interaction partners in colon cancer.ConclusionsOur results identify increased expression of L1TD1 as a prognostic marker predicting longer disease-free survival in colon cancer patients.

Mucin 16 and kallikrein 13 as potential prognostic factors in colon cancer: Results of an oncological 92-multiplex immunoassay.

Colon cancer represents one of the most common cancers in the world. Despite improved treatment, mortality remains high. In order to improve the assessment of prognosis for colon cancer patients, identifying new prognostic markers remains necessary. We analyzed preoperative serum samples from 148 colon cancer patients surgically treated at Helsinki University Hospital from 1998 through 2002 using a multiplex proximity extension assay (Oncology II panel, Olink Bioscience, Uppsala, Sweden), a panel constituting 92 immunological and oncological markers. We performed univariate and multivariate analyses on these patients and calculated the disease-specific survival among patients using the log-rank test for Kaplan-Meier estimates. In the univariate survival analysis of 92 biomarkers, 26 resulted in p < 0.1. Among these, eight biomarkers emerged as statistically significant (p < 0.05). Patients with low levels of kallikrein 13 had a poor prognosis. Moreover, patients with high levels of amphiregulin, carcinoembryonic antigen-related adhesion molecule 5, interleukin 6, mucin 16, syndecan 1, transforming growth factor alpha, and vimentin also had a poor prognosis. In the multivariate analysis, kallikrein 13 and mucin 16 emerged as independent prognostic markers. The role of kallikrein 13, a member of the serine protease kallikrein biomarker family, in tumorigenesis remains unclear. Mucin 16 is also known as carbohydrate antigen 125, a well-known ovarian cancer biomarker. Patients with low levels of kallikrein 13 (hazard ratio: 0.36; 95% confidence interval: 0.14-0.92; p = 0.033) and high levels of mucin 16 (hazard ratio: 3.15; 95% confidence interval: 1.68-5.93; p < 0.005) had a poor prognosis. Mucin 16 and kallikrein 13 represent independent prognostic markers for colon cancer. Furthermore, the clinical utility of mucin 16 and kallikrein 13 serum tests warrants additional investigation.

Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

Background The tumor stroma plays pivotal roles in influencing tumor growth, invasion, and metastasis. Transcriptional signatures of colon tumor stroma (CTS) are significantly associated with prognosis of colon cancer. Thus, identification of the CTS transcriptional features could be useful for colon cancer diagnosis and therapy. Methods By a meta-analysis of three CTS gene expression profiles datasets, we identified differentially expressed genes (DEGs) between CTS and colon normal stroma. Furthermore, we identified the pathways, upstream regulators, and protein-protein interaction (PPI) network that were significantly associated with the DEGs. Moreover, we analyzed the enrichment levels of immune signatures in CTS. Finally, we identified CTS-associated gene signatures whose expression was significantly associated with prognosis in colon cancer. Results We identified numerous significantly upregulated genes (such as CTHRC1, NFE2L3, SULF1, SOX9, ENC1, and CCND1) and significantly downregulated genes (such as MYOT, ASPA, KIAA2022, ARHGEF37, BCL-2, and PPARGC1A) in CTS versus colon normal stroma. Furthermore, we identified significantly upregulated pathways in CTS that were mainly involved in cellular development, immune regulation, and metabolism, as well as significantly downregulated pathways in CTS that were mostly metabolism-related. Moreover, we identified upstream TFs (such as SUZ12, NFE2L2, RUNX1, STAT3, and SOX2), kinases (such as MAPK14, CSNK2A1, CDK1, CDK2, and CDK4), and master metabolic transcriptional regulators (MMTRs) (such as HNF1A, NFKB1, ZBTB7A, GATA2, and GATA5) regulating the DEGs. We found that CD8+ T cells were more enriched in CTS than in colon normal stroma. Interestingly, we found that many of the DEGs and their regulators were prognostic markers for colon cancer, including CEBPB, PPARGC1, STAT3, MTOR, BCL2, JAK2, and CDK1. Conclusions The identification of CTS-specific transcriptional signatures may provide insights into the tumor microenvironment that mediates the development of colon cancer and has potential clinical implications for colon cancer diagnosis and treatment.

The clinical impact of miRNA34a and P53 gene expression in colon cancer

ObjectiveTo study the potential role of miRNA34a gene expression and its relationship with P53 gene expression, fate, stage, metastasis and overall survival of colorectal cancer. Patients and methodsThis study was carried out 30 patients with colon adenocarcinoma, 30 patients with benign colon polyp and 30 apparently healthy persons served as controls. All participants were subjected to full history taking, general clinical examination. Complete blood count, liver and kidney function, determination of serum tumor markers were done. Estimation of microRNA 34a and P53 Gene expression by real-time PCR were done. ResultsThere was a significant negative relationship between serum tumor markers and micro RNA 34a gene expression in cancer patients. Also, there was a statistically significant positive relationship between miRNA34a gene expression and P53 gene expression in both patients groups. The diagnostic accuracy of miRNA34a gene expression was both sensitive and specific for colon cancer. MiRNA34a and P53 gene expression had statistically significant relation with tumor stage and presence of metastases. ConclusionIt can be concluded that the level of miRNA34a can be used to differentiate between colon cancers and begin adenomas. MiRNA34a can be used as a prognostic marker in colon cancer.

Microsatellite instability as a predictive marker for response to neoadjuvant chemoradiation in locally advanced rectal cancer.

806 Background: Microsatellite instability (MSI) is a marker for hypermutability due to impaired DNA mismatch repair and has been shown to be a favorable prognostic marker in colon cancer. We examined the role of MSI in locally advanced rectal cancer (LARC) as a predictive marker for response to neoadjuvant chemoradiation (CRT). Methods: We identified T3-T4 or ≥ N1 rectal cancer with reported MSI status in the National Cancer Data Base from 2007 – 2012. Patients were eligible if they were treated with CRT followed by surgical resection. Squamous cell and carcinoid histologies were excluded. The primary outcome was neoadjuvant rectal (NAR) score, categorized as low ( &lt; 8), intermediate (8-16), and high ( &gt; 16), representing a good, intermediate, and poor response to CRT, respectively. The secondary outcomes were complete pathologic response (ypCR) rate and overall survival (OS). Chi-square, Fisher’s exact, and independent sample t-tests were used to compare MSI status. Multivariable logistic regression models were used to examine factors associated with increasing level of NAR score and ypCR. OS was examined using multivariable Cox proportional hazards models. Results: A total of 1849 patients were eligible for the study and were classified as MSI-high (n = 52) or MSI-low/stable (n = 1797). Patients in the MSI-high group were younger (median age 50.5 vs 57.0, p = 0.005) and had higher rates of mucinous and signet ring histology (p &lt; 0.001), clinical T4 disease (p = 0.001), and clinically positive lymph nodes (p = 0.049). The two groups did not differ in gender, race, grade, or resection margin status. While clinical T and N stage, histology, LVI, tumor grade, and PNI were correlated with the NAR score groups, MSI-high status was not significantly associated with a higher NAR score group on multivariable analysis (OR 1.168, 95% CI 0.673 – 2.028). The MSI-high group also did not differ significantly from MSI-low/stable group in ypCR rate (OR 0.748, 95% CI 0.179 – 3.115) or OS (HR 1.727, 95% CI 0.864 – 3.453) on multivariable analysis. Conclusions: MSI status in LARC was not associated with NAR score, ypCR rate, or OS. Our results do not support the use of MSI status as a predictive marker for response to CRT in LARC.

Carcinoembryonic antigen levels of tumor-draining venous blood as a prognostic marker in colon cancer

Purpose Carcinoembryonic antigen (CEA) is a tumor marker for colorectal cancer (CRC) related to recurrence and prognosis. We examined the ability of the CEA level measured directly from a tumor drainage vein (dCEA) to predict the prognosis of CRC more accurately than those from a peripheral vein (pCEA). Methods Fifty-two patients who received curative resection for colon adenocarcinoma were enrolled. The patients were categorized into two groups according to normal pCEA (<5.9425 ng/mL, n=24) or elevated pCEA levels (≥5.9425 ng/mL, n=28). Blood was sampled at the time of surgery simultaneously from the tumor drainage vein and from the peripheral vein. Results The clinicopathologic variables showed no significant difference between the two groups. Patients with dCEA levels <20.192 ng/mL showed better disease-free (P=0.009) and overall survival (P=0.033) curves than those with dCEA levels ≥20.192 ng/mL. Elevated dCEA levels were a significant prognostic factor for overall survival and disease-free survival in Cox proportional hazard model analysis (hazard ratio [HR]=399; 95% confidence interval [CI], 16.4–9,747; P<0.001; HR=9.39, 95% CI, 1.29–68.006; P=0.026). In subgroup analysis, we compared the data of normal range of dCEA group and elevated dCEA group with normal pCEA; the overall survival rate of patients with normal dCEA was better and the disease-free survival rate was significantly better (P=0.003). Conclusion CEA levels from a tumor drainage vein can be used as more accurate prognostic markers than levels from a peripheral vein in patients with colon cancer. Keywords: Carcinoembryonic antigen, Prognosis, Colorectal cancer

MicroRNA-449a deficiency promotes colon carcinogenesis

MicroRNAs have broad roles in tumorigenesis and cell differentiation through regulation of target genes. Notch signaling also controls cell differentiation and tumorigenesis. However, the mechanisms through which Notch mediates microRNA expression are still unclear. In this study, we aimed to identify microRNAs regulated by Notch signaling. Our analysis found that microRNA-449a (miR-449a) was indirectly regulated by Notch signaling. Although miR-449a-deficient mice did not show any Notch-dependent defects in immune cell development, treatment of miR-449a-deficient mice with azoxymethane (AOM) or dextran sodium sulfate (DSS) increased the numbers and sizes of colon tumors. These effects were associated with an increase in intestinal epithelial cell proliferation following AOM/DSS treatment. In patients with colon cancer, miR-449a expression was inversely correlated with disease-free survival and histological scores and was positively correlated with the expression of MLH1 for which loss-of function mutations have been shown to be involved in colon cancer. Colon tissues of miR-449a-deficient mice showed reduced Mlh1 expression compared with those of wild-type mice. Thus, these data suggested that miR-449a acted as a key regulator of colon tumorigenesis by controlling the proliferation of intestinal epithelial cells. Additionally, activation of miR-449a may represent an effective therapeutic strategy and prognostic marker in colon cancer.

Abstract A83: Digital quantitative immunohistochemistry for analysis of CCSP-2 and 15-PGDH expression in colon cancer

Abstract The analysis using quantitative immunohistochemistry (IHC) with diagnostic and prognostic biomarkers is a powerful tool for scientific and clinical research in colon cancer at early stages. The potential utility of distinct protein expression depending on the stages of colon cancer has generated interest in diagnostic and prognostic biomarkers of colon cancer. Colon cancer secreted protein-2 (CCSP-2) has been reported as a novel protein expressed in colon adenomas and cancers but not in normal colon tissue. Thus, this protein has emerged as a potential prognostic marker at early stages. In addition, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been useful as a diagnostic or prognostic marker for colon cancer. To clarify the assessment parameters for CCSP-2 and 15-PGDH in colon cancer, we evaluated its clinical, molecular and survival associations in colon cancer, according to stages of colon cancer and the tumor microenvironment, such as immune cells, by multiplex immunohistochemistry. Formalin fixed paraffin embedded (FFPE) samples of patients' primary tumor were obtained and stained for markers include CD3, CD8, Cytokeratin, Ki-67, CCSP-2 and 15-PGDH by using PerkinElmer Opal system. Digital imaging and analysis were done using PerkinElmer Nuance and Inform software system. Density plot analysis revealed distributions of CCSP-2 and 15-PGDH in colon cancer tissues. The expression of CCSP-2 and 15-PGDH correlated with stages of colon cancer. Thus, CCSP-2 and 15-PGDH, as proteins that distinctly expressed in colon adenomas and adenocarcinomas, may be useful diagnostic and prognostic markers for detection of colorectal tumors. Citation Format: GyeongMin Park, Charles Jungje Cho, Ji-Young Shin, Eun-Ju Do, Yeon-Mi Ryu, Gil-Je Lee, Sang-Yeob Kim, Youngkuk Yun, Seung-Jae Myung. Digital quantitative immunohistochemistry for analysis of CCSP-2 and 15-PGDH expression in colon cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A83.