Prognosis Of CRC Research Articles

Primary Tumor Location as a Prognostic and Predictive Marker in Metastatic Colorectal Cancer (mCRC).

Clinico-pathological differences between adenocarcinoma in the right and left colo-rectum play a role in determining the prognosis and response to treatment. Studies suggest that primary tumor location is more relevant as the disease progresses and reflects a possible difference in biology and response to therapy. This review aims to explore the clinico-pathological features of right and left colo-rectum and the impact of primary tumor location on prognosis of CRC as well as discuss the available clinical data on tumor sidedness in metastatic colorectal cancer. In so far as the clinical data of tumor sidedness is concerned, very few reviews have discussed the clinical implications of sidedness in heavily pre-treated metastatic colorectal cancer (second and subsequent lines of therapy in metastatic disease). This review aims to fill the current gap in this setting.

Colorectal Cancer Immune Infiltrates: Significance in Patient Prognosis and Immunotherapeutic Efficacy.

Colorectal cancer occurrence and progression involve multiple aspects of host immune deficiencies. In these events, immune cells vary their phenotypes and functions over time, thus enabling the immune microenvironment to be “tumor-inhibiting” as well as “tumor-promoting” as a whole. Because of the association of tumoricidal T cell infiltration with favorable survival in cancer patients, the Immunoscore system was established. Critically, the tumoral Immunoscore serves as an indicator of CRC patient prognosis independent of patient TNM stage and suggests that patients with high Immunoscores in their tumors have prolonged survival in general. Accordingly, stratifications according to tumoral Immunoscores provide new insights into CRC in terms of comparing disease severity, forecasting disease progression, and making treatment decisions. An important application of this system will be to shed light on candidate selection in immunotherapy for CRC, because the T cells responsible for determining the Immunoscore serve as responders to immune checkpoint inhibitors. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration of cytotoxic and memory T cells, while information concerning the survival and function of these cells is still absent. Moreover, other infiltrates, such as dendritic cells, macrophages, and B cells, can still influence CRC prognosis, implying that those might also influence the therapeutic efficacy of immune checkpoint inhibitors. On these bases, this review is designed to introduce the Immunoscore system by presenting its clinical significance and application in CRC.

Endoglin (CD105) and VEGF as potential angiogenic and dissemination markers for colorectal cancer

BackgroundColorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer.Material and methodsThis study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9 months after resection of the tumor.ResultsVEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumors.ConclusionEndoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.

Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer.

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

BackgroundColorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear.MethodsTo explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC.ResultsWe found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways.ConclusionsThese findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.

Genetic Variants of HOTAIR Associated With Colorectal Cancer Susceptibility and Mortality.

In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case–control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052–1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189–7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435–9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.

IL-36\u2009s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer?

Background and aimsColorectal cancer (CRC) is a major killer. Host immunity is important in tumorigenesis. Direct comparison among IL-36α, IL-36β and IL-36γ in the prognosis of CRC is unclear.MethodsCRC tissue arrays were generated from colorectostomy samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, IL-36α, IL-36β and IL-36γ were determined, in comparison to non-cancer tissues.ResultsA significant association was observed between colonic IL-36α, IL-36β or IL-36γ and the presence of cancer (with all P < 0.0001). Using ROC curve analysis, specificity and sensitivity of IL-36α, IL-36β or IL-36γ were confirmed, with area under the curve (AUC) values of 0.68, 0.73 and 0.65, respectively. Significant differences in survival were observed between IL-36αhigh and IL-36αlow (P = 0.003) or IL-36γhigh and IL-36γlow (P = 0.03). Survival curves varied significantly when further stratification into sub-groups, on the basis of combined levels of expression of two isotypes of IL-36 was undertaken. A significant difference was observed when levels of IL-36α and IL-36β were combined (P = 0.01), or a combination of IL-36α plus IL-36γ (P = 0.002). The sub-groups with a combination of IL-36αhigh plus IL-36βhigh, or IL-36αhigh plus IL-36γlow exhibited the longest survival time among CRC patients. In contrast, the sub-groups of IL-36αlow plus IL-36βhigh or IL-36αlow plus IL-36γhigh had the shortest overall survival. Using the log-rank test, IL-36αhigh expression significantly improved survival in patients with an invasion depth of T4 (P < 0.0001), lymph node metastasis (P = 0.04), TNM III-IV (P = 0.03) or with a right-sided colon tumour (P = 0.02). Similarly, IL-36γlow expression was significantly associated with improved survival in patients with no lymph node metastasis (P = 0.008), TNM I-II (P = 0.03) or with a left-sided colon tumour (P = 0.05). Multivariate analysis demonstrated that among IL-36α, IL-36β and IL-36γ, only IL-36α (HR, 0.37; 95% CI, 0.16–0.87; P = 0.02) was an independent factor in survival, using Cox proportional hazards regression analysis.ConclusionIL-36α or IL-36γ are reliable biomarkers in predicting the prognosis of CRC during the later or early stages of the disease, respectively. Combining IL-36α plus IL-36γ appears to more accurately predict the postoperative prognosis of CRC patients. Our data may be useful in the management of CRC.

Overweight is associated with better prognosis in metastatic colorectal cancer patients treated with bevacizumab plus FOLFOX chemotherapy.

IntroductionPrevious studies showed that high and low body mass index (BMI) was associated with worse prognosis in metastatic CRC (mCRC). Whether BMI is a prognostic or predictive factor in mCRC is unclear. We aimed to assess efficacy outcomes according to BMI in patient with metastatic colorectal cancer treated with bevacizumab plus FOLFOX chemotherapy regimen in second-line treatment.Material and methodsThe analysis of 237 patients with metastatic colorectal cancer treated with bevacizumab plus FOLFOX in the second line (treated from January 2014 to August 2018) in 4 reference oncological centers in Poland.ResultsThe median age of the patients was 65 years (range 34–82). The median overall survival (OS) and progression-free survival (PFS) of the all 237 patient was 14.6 and 8.8 months, respectively. Comparison of obese patient (BMI > 30 kg/m2) vs. overweight patients (BMI ≥ 25 to < 30 kg/m2) vs. normal BMI range patients revealed a significant improvement of median OS (17.5 vs. 14.3 vs. 13.1 months, p = 0.01) and median PFS (9.4 vs. 9.1 vs. 7.3 months, p = 0.03). The Cox hazard model showed that the BMI class is an important risk factor. However, the Cox model also showed that the significance of the BMI class applies only to patients with BMI < 25 kg/m2. This rule applies to both OS and PFS. The regression analysis also confirmed that there is a statistically significant relationship between the length of OS and PFS and the BMI value. Higher BMI was associated with a better prognosis. There were no differences in responses to treatment bevacizumab and FOLFOX chemotherapy and number adverse events according to BMI values.ConclusionsPatients with mCRC treated with chemotherapy with bevacizumab in second-line treatment with higher BMI compared with normal weight patients have better prognosis in terms of PFS and OS. In this group, we found no evidence of changes in safety profile depending on BMI. Nevertheless, further large randomized studies are needed to assess the body weight on the effectiveness of chemotherapy in combination with bevacizumab.

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis.

CHIP and Galectin-1 are associated with the development of metastasis in cancer. However, the precise roles of CHIP or Gal1 in colorectal cancer are uncertain. Here, our study explored the relationship and clinical significance of CHIP or Gal1 in CRC. CHIP or Gal1 expression was significantly decreased or up-regulated in CRC compared with adjacent noncancerous tissues by immunohistochemistry on a CRC tissue microarray, respectively. Low CHIP or high Gal1 expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival. Multivariate Cox regression analysis revealed that CHIP or Gal1 expression was an independent prognostic factor for CRC patients. Moreover, CHIP associated with Gal1 has a synergistic effect on the prediction of CRC prognosis. In vitro and vivo, high CHIP or low Gal1 expression inhibit CRC growth or metastasis. Our results found that CHIP could degradate Gal1 by ubiquitination. In summary, CHIP could inhibit CRC growth or metastasis through promoting Gal1 ubiquitination and degradation by proteasome. CHIP and Gal1 expressions are novel candidate prognostic markers in CRC. A combined effect of CHIP and Gal1 as efficient prognostic indicators was found for the first time.

Variations in AXIN2 predict risk and prognosis of colorectal cancer

ObjectiveColorectal cancer (CRC) and hypodontia are frequent and different diseases with common genes are involved in their etiology. The objective of this study was to identify the association between AXIN2 rs2240308 with hypodontia and CRC.Patients and methodsThis study consisted of 50 individuals with hypodontia, 50 individuals with CRC, and 155 healthy individuals from Colombia. SNP genotyping assays of rs2240308 were performed and family history of cancer in individuals with hypodontia was documented. In silico analysis was implemented to define the genomic profile of the AXIN2 gene associated with CRC. Multivariate analysis, chi square, odd ratio tests, and R software were used for statistical analysis.ResultsAXIN2 rs2240308 showed association with CRC (OR = 5.4 CI: 2.7–10.4; p < 0.001) and with other familial cancer in individuals with hypodontia (p < 0.005 OR = 1.75, 95% CI: 1.22–6.91). In silico analysis showed that variations in AXIN2 found in CRC patients, were more frequently in earlier stages of tumor and patients who carry variations in the AXIN2 gene have a worse prognosis (p < 0.05). The association between AXIN2 rs2240308 with hypodontia was not significant.ConclusionsThese results suggest that AXIN2 rs2240308 polymorphism is associated with CRC and AXIN2 could be a risk marker for predisposition and prognosis of CRC.

Efecto de la demora atribuible al sistema sanitario en el pronóstico del cáncer colorrectal

ObjectivesTo analyse the effect of a delay attributable to the healthcare system on a consecutive cohort of outpatients diagnosed with colorectal cancer in the healthcare area of Ourense (Spain). Patients and methodsWe performed a retrospective cohort study that included patients diagnosed between 2009 and 2017. Delay attributable to the healthcare system was defined as the time between the first consultation with symptoms and the diagnostic confirmation. A logistic regression model was performed to evaluate the relationship between stage IV CRC and diagnostic delay. To analyse which variables were associated independently with overall mortality and mortality due to CRC we used a Cox regression model. Results575 patients were included (men 64.5%, age 71.9 ± 11.5 years), with a delay attributable to the healthcare system of 115 ± 153 days. None of the variables analysed were associated with tumour stage at diagnosis. With a mean follow-up of 30.6 ± 21 months, 121 patients died (79.3% due to CRC). The variables independently associated with CRC-related mortality were metastatic CRC (HR 50.65, 95% CI 12.28-209), age (HR 1.04, 95% CI 1.02-1.05) and colonoscopy requested from the Primary Healthcare level (HR 0.55, 95% CI 0.36-0.88). ConclusionsDiagnostic delay attributable to the healthcare system is not related to the prognosis or stage of CRC. However, a direct referral to colonoscopy from the Primary Healthcare level reduces the risk of mortality in our patients.

The role of P2X7 receptor in prognosis and metastasis of colorectal cancer

PurposeColorectal cancer (CRC) is one of the leading causes of cancer mortality in the world. P2X7 receptor (P2X7R), encoded by the P2rx7 gene, is a trimeric ion channel activated by extracellular Adenosine triphosphate and is widely expressed in various types of tissues and tumors to regulate inflammation, cell proliferation, or death. The discovery of new biomarkers and understanding the role of P2X7R in CRC are therefore critical to improving the prognosis and treatment of CRC. Materials and methodsP2X7R expression was analyzed in CRC tumor samples and normal colorectal tissues from 97 patients and various colon cancer cell lines. The correlation of tumor antigens, survival periods, and P2X7R expression were documented. ResultsP2X7RHigh and P2X7RLow populations were observed in CRC patients. P2X7RHigh patients had relatively shorter survival periods, higher levels of serum carcinoembryonic antigen, and greater numbers of advanced tumors. In addition, P2X7R expression had a significant up-regulation in metastatic CRC and metastatic CRC cell lines, which indicates that P2X7R expression is positively associated with metastasis. ConclusionsP2X7R expression might be a potential biomarker for prognosis and metastasis of CRC.

Abstract 720: Aspirin plus FOLFOX for colorectal cancer management: A promising alternative for clinical trial in Africans with the disease

Abstract Colorectal cancer (CRC) has disproportionately overburden Africans with advanced stage at diagnosis and higher mortality rate due in part to issues that include grossly inadequate resources for management and poor understanding of the pathobiology of the disease. Accumulating evidences support the effectiveness of Aspirin in prevention and inhibition of CRC occurrence and cellular growth respectively. The utilisation of 5-fluorouracil (5-FU)-based regimens which include folinic acid, 5-FU and oxaliplatin (FOLFOX) combination in CRC management have not completely halt the distant recurrences and poor prognosis of CRC. In this study, we highlighted evidences that prove Aspirin plus FOLFOX to be promising alternative for clinical trial in Black men with CRC. Our study aims in this research were: to identify the expression pattern of BIRC7 in human CRC cells, SW480 cell line and N-methyl-N-nitrosourea (NMU)-induced CRC in rat; to determine the relationship between BIRC7 and BCL2, p53, PDL-1, MSH1, PMS2, DARC and Annexin V expression in CRC. to examine the efficacy of Aspirin plus neoadjuvant FOLFOX on the BIRC7 in CRC cells in-vivo in rat. Results show significant (P = 0.0001) expression of the BIRC7 in the CRC tissues compared to normal sections. When comparing this expression with Data from TCGA data bank, we observed a significant increase in BIRC7 expression in Caucasian than the Black and Indian and The expression pattern of the BIRC7 was significantly higher (P = 0.0001) in CRC not otherwise specified compared to mucinous CRC histology. The SW480 cell line show increased expression of the BIRC7 protein in-vitro. There was significant expression of the BIRC7 in the NMU-induced CRC cells compared the normal colonic lesion. There was increased expression of the BCL-2 and reduced expression of p53 in the human CRC cases and in the NMU-induced CRC cells model. There was increased expression of the Annexin V, absence of the MSH1, PMS2, PDL1 and DARC protiens in the CRC sections. Aspirin plus FOLFOX may serve as an important adjuvant treatment component for colorectal cancer metastasis and local recurrence in Blacks, Caucasian and Asians. There is need to explore the potential of Aspirin plus FOLFOX for clinical trial in colorectal cancer management in Blacks and other population using approach from our findings. Citation Format: Faruk Mohammed, Sani Ibrahim, Sirajo Mohammed Aminu, Ahmed Adamu, Adamu Abdullahi, Abdulmumini Hassan Rafindadi, Yawale Iliyasu, John Idoko, Abdullahi Jubril Randawa, Mohammed Sani Shehu, Atara Ntekim, Abdullahi Mohammed, Aishatu Maude Suleiman, Yahaya Ukwenya, Khalid Zahir Shah, Ahmad Bello, Sani Abubakar, Kasimu Umar Adoke, Cheh Augustin Awasum, Ahmad Mai, Hussaini Yusuf Maitama, Dauda Maigatari. Aspirin plus FOLFOX for colorectal cancer management: A promising alternative for clinical trial in Africans with the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 720.

ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer

Most of colorectal cancer CRC-related death is due to metastasis and the finding of markers for prognosis of invasiveness, constitutes an appealing challenge. Here, after analysing cDNA array containing 43 tumour and 5 normal mucosa samples, we report that the expression of the ZNF518B gene as a whole and that of its two major splicing isoforms are significantly increased in tumours. The canonical isoform was also up-regulated in a patients’ cohort containing 70 tumour and 69 adjacent tissue samples. The effects of silencing ZNF518B on the phenotype of CRC cell lines were then studied. The gene does not affect cell proliferation, but plays a significant role in cell migration and invasiveness and induces changes in the epithelial-to-mesenchymal transition markers, suggesting that ZNF518B favours tumour cell dissemination. To study the regulation of the gene, transcription-related changes in nucleosomal organisation and epigenetic marks around the transcriptional start site were analysed. The positioning of a nucleosome over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with gene expression. Inhibition of histone deacetylases increases the transcription of ZNF518B, which may be a candidate for invasiveness prognosis in CRC and a target for epigenetic drugs.

Mutation profiling of BRAF gene in Chinese patients with early or advanced colorectal cancer using comprehensive NGS panel.

e15124 Background: It has been reported that BRAF gene mutation occurs in approximately 10% of metastatic colorectal cancer (mCRC), and is associated with resistance to EGFR inhibitors. Moreover, patients with non-V600E BRAF mutations with a better prognosis than patients with V600E BRAF mutations in advanced colorectal cancer. However, little is known about mutation profiling of BRAF in early stage colorectal cancer. Methods: We reviewed mutation profiling of 1429 colorectal cancer samples in our institute from 2016 to 2018. Tissue biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59-1021 genes). Results: A total of 1429 samples from 1120 patients with CRC, included 86 early stage (Ⅰ-Ⅱ ), 966 advanced stage (Ⅲ -Ⅳ), and 377 samples with unknown stage. We identified 109 samples from 94 patients with BRAF gene mutation in the cohort (109/1429=7.63%), of which V600E and non-V600E were 62(4.34%) and 47 (3.29%), respectively. Among the 109 samples, there were 15 of early stage, 84 of advanced stage and 10 of unknown stages. BRAF mutation were more common in early CRC samples (15/86=17.44%) than in advanced CRC samples (84/966=8.7%, p = 0.007). Furthermore, 10 of the 15 early CRC samples yet 32 of the 84 mCRC samples had non-V600E were detected (66.67% vs 38.1%, p=0.039). In contrast to V600E mutation, some of the non-V600E variants were variants of unknown clinical significance (VUS) in this study (see Table). Conclusions: BRAF mutation is more common in early stage CRC, the higher prevalence of non-V600E BRAF mutations in early CRC may account for the better prognosis of early stage CRC. non-V600E BRAF mutation subtype. [Table: see text]

Multivariate analysis of genes expressed in the colorectal tumor immune microenvironment driven by CXCL13

Abstract Colorectal cancer (CRC) is a heterogenous disease having numerous molecular phenotypes. Key tumor progression markers such as microsatellite instability, BRAF, and KRAS mutation status have been widely studied. Less is known regarding the influence of chemokines and chemokine receptors in CRC. CXCL13 and CXCR5 have been shown to be associated with poor prognosis of advanced CRC. The central hypothesis tested in this study was CXCR5-CXCL13 signaling mediates gene expressions associated with CRC progression. RNAseq patient control and matched primary tumor samples were acquired from The Cancer Genome Atlas (TCGA). DESeq analysis identified differentially expressed genes between normal tissue and primary tumor groups. Weighted Gene Co-expression Network Analysis (WGCNA) elucidated gene networks that correlated with factors influencing CRC prognosis. Canonical pathway, upstream regulator, and protein-protein interaction analyses were performed using Ingenuity Pathway Analysis (IPA). CXCL13 was identified in the WGCNA-designated green module, which also contained XCL1, TNFRSF17, FCRN1, CCL19, IL-17A and IFNG. These genes are associated with immunoregulatory signals found in lymphoid and non-lymphoid cells, BCR-signaling and poor prognosis of CRC. Genes associated with energy metabolism, apoptosis, hypoxia and angiogenesis, including GNG4, PRKCG, WNT11, and KNG1, were found in the WCGNA-designated yellow module. These factors are involved in Wnt/CTNNNB1 and PI3K/AKT signaling, which have previously shown to be driven by CXCR5-CXCL13 interactions. Taken together, our data suggest a role of the CXCL13-CXCR5 axis in shaping the tumor immune microenvironment of CRC.

Impact of primary colorectal Cancer location on the KRAS status and its prognostic value

BackgroundColorectal cancer (CRC) originating from the right-sided or left-sided colon is distinct clinicopathological entity. The KRAS status and its prognostic value in CRC remain controversial. This study aimed to investigate the association of KRAS status with clinicopathological features and prognostic value in CRC.Methods178 colon cancer and 145 rectal cancer patients were enrolled. KRAS mutation test was performed on paraffin-embedded tumor samples using PCR methods. The colon cancer was divided into right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Studies that reported the association of KRAS mutation with CRC clinical features and prognosis in databases were searched prior to 2018. The data of the present study was combined with the data of published studies using meta-analysis methods.ResultsNo significant difference between colon cancer and rectal cancer regarding the KRAS status. The KRAS mutation was much frequent in RCC than in LCC (p = 0.010). 17 studies with 11,385 colon cancer patients were selected, the pooled results of our data and previous published data showed that KRAS mutation was more frequent in RCC compared with in LCC (p < 0.01); KRAS mutation was not associated with the prognosis in RCC patient; however, KRAS mutation indicated a poor prognosis in LCC patients compared with KRAS wild type (p < 0.01).ConclusionKRAS status has no difference between colon cancer and rectal cancer. KRAS mutation was more frequent in RCC than in LCC, and associated with a poor prognosis in LCC patients, but not in RCC patients.

Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

564 Background: Large metagenomic studies associate disrupted gut microbiome signatures, comprising more prevalently gram-negative bacteria, with CRC carcinogenesis. TLR4, the LPS receptor, has been involved in microbiota-mediated tumorigenesis. High TLR4 expression is associated with poor prognosis in CRC and TLR4 can activate EGFR through ligands epiregulin and amphiregulin. Hence, we hypothesized that genetic variants in the LPS receptor complex and TLR4 expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 5 functional SNPs within TLR4, MD2 and CD14 was analyzed in 129 pts treated with first-line FOLFIRI/cet (discovery, mPFS/OS: 12.8/49.8 mo) and 107 pts treated with FOLFIRI/bevacizumab (bev) (mPFS/OS: 11.5/31.4 mo). Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the discovery cohort, pts carrying the C/T variant of TLR4 rs4986791 had significantly shorter mPFS and OS compared to the C/C genotype in both uni- and multivariable analysis (PFS: 5.4 vs 13.3 mo, adjusted P[ Padj] = .01; OS: 21.7 vs 40.7 mo, Padj= .03). Conversely, C/C carriers of rs12377632 had a longer mPFS compared to any T in uni- and multivariable analysis (15.8 vs 12.2 mo, Padj&lt; .001). Any A allele carriers of MD2 rs12546552 and any G allele carriers of CD14 rs2569190 showed shorter mPFS in multivariable analyses. These associations were not observed in bev arm. Significant interaction was found between TLR4 rs12377632 and RAS status ( P= .015). High TLR4 expression (log2 &gt; 10.93) was associated with worse mPFS (7.2 vs 11 mo, P= .003) and OS (19.1 vs 29.8 mo, P&lt; .001) in FIRE-3 cet arm. Conclusions: Our results provide the first evidence that polymorphisms in the LPS receptor complex and TLR4 expression levels may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and, overall, contribute to resistance to anti-EGFRs.

Long noncoding RNA GIHCG induces cancer progression and chemoresistance and indicates poor prognosis in colorectal cancer.

BackgroundColorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, however, the mechanisms of CRC progression remain obscure. The present study investigated the clinical significance and functional role of long noncoding RNA (lncRNA) GIHCG in CRC.MethodsExpression of GIHCG was detected by quantitative real time polymerase chain reaction (qRT-PCR) in seven CRC cell lines and 110 CRC tissues. Comparison of clinicopathological characteristics in the high GIHCG expression group and the low GIHCG expression group was performed. The overall survival (OS) and progression-free survival (PFS) of the patients were depicted with Kaplan-Meier test and compared with Log-rank test. Univariate and multivariate analyses were carried out to detect the risk factors for poor OS and PFS. In addition, expression of GIHCG was silenced with siRNAs in LoVo cells and overexpressed with pcDNA3.1-GIHCG vector in SW480 cells, respectively. And the Transwell assay, Matrigel assay, colony formation assay and Cell Counting Kit-8 assay (CCK-8) were performed to investigate the role of GIHCG in the migration, invasion and proliferation of CRC cells. Besides, the role of GIHCG in chemoresistance was also detected.ResultsGIHCG was overexpressed in seven CRC cell lines and 110 CRC tissues. High GIHCG expression was correlated with lymphovascular invasion, lymph node metastasis, distant metastasis and advanced TNM stages. Moreover, patients with high GIHCG expression had much poorer OS and PFS rates. Besides, high GIHCG expression was identified as an independent risk factor for poor OS and PFS. The Transwell assay and the Matrigel assay discovered that GIHCG deficiency inhibited cell migration and invasion, while ectopic expression of GIHCG promoted migration and invasion. Besides, the colony formation assay and the CCK-8 assay verified that GIHCG increased cell proliferation ability. By establishing 5-fluorouracil (5-FU) and Oxaliplatin (Oxa)-resistant LoVo cells and SW480 cells, we found chemoresistant CRC cells had much higher expression levels of GIHCG. Also, GIHCG facilitated cell survival under 5-FU or Oxa treatment. Furthermore, silencing of GIHCG notably reduced the improved cell survival rates of 5-FU or Oxa-resistant LoVo cells compared with control cells.ConclusionGIHCG contributes to cancer progression and chemoresistance and indicates poor prognosis in CRC. GIHCG may be a promising prognostic biomarker and therapeutic target in CRC.

TIMP-2 inhibits metastasis and predicts prognosis of colorectal cancer via regulating MMP-9

ABSTRACTColorectal cancer has a common cause of morbidity and mortality. Therefore, it is urgent to detect reliable biomarkers to predict prognosis in CRC. Here, we determined the expression of TIMP-2 and MMP-9 in a CRC tissue microarray by immunohistochemistry. We found that lower TIMP-2 or/and higher MMP-9 expression in cancer tissues was correlated with poorer overall survival (OS). TIMP-2 or MMP-9 expression was independent prognostic factors for CRC. Furthermore, TIMP-2 and MMP-9 expression had a synergistic role as efficient prognostic indicators for CRC patients. In vitro and in vivo, TIMP-2 could inhibit HCT 116 cells invasion and migration by regulating MMP-9. In sum, a combined expression of TIMP-2 and MMP-9 as efficient prognostic indicators was found for the first time.