Prognostic Factor In Colorectal Cancer Research Articles

Survey of Neutrophil to Lymphocyte Ratio as Prognostic Factor in Colorectal Cancer

Background: Neutrophil-lymphocyte ratio (NLR) is derived from the neutrophil and lymphocyte count obtained from routine complete blood count with the differential test (CBC/diff). The aim of the present study is to determine the relationship between NLR with prognostic factors in colorectal cancer. Material and Methods: A total of 70 patients with colorectal cancer were studied according to the research objectives. Independent T-test and Mann-Whitney U Mann-Whitney test were used to compare the NLR with qualitative variables such as pathology type. Pearson or Spearman correlation coefficient was used for correlating the quantitative variables. The significance level was considered as P<0.05. Results: Most of the enrolled patients were in the age group of 60-69 years (31.5%). The mean and standard deviation of NLR was 2.1 ± 0.1. Only 4.3% of the subjects had NLR greater than 5. The association between NLR with N-stage (P=0.005) and inflammatory factor (CRP) was statistically significant (P = 0.016). The correlation between NLR and these variables showed that Grade (P=0.091), PNI (P=0.093), LDH (P=0.20), diabetes (P=0.264), M-stage (P=0.282), ESR (P=0.386), LVSI (P=0.473), T-stage (P=0.527), CEA (P=0.582), and BMI (P=0.681) with NLR was not meaningful. Conclusion: NLR can be associated with prognosis and risk of disease progression, especially in lymph nodes. Since NLR does not require additional testing and request and is quite easy and cost-effective, it is recommended considering this ratio during the initial assessment and the classification of the risk and stage of the disease.

312 Patients With Very Early Onset Colorectal Cancer Have Increased Microsatellite Instability

INTRODUCTION: The incidence of colorectal cancer (CRC) in young patients has been increasing. This has led to increase interest in the molecular patterns and epigenetics of CRC in this age group. Microsatellite instability has been noted to be a positive prognostic factor in CRC. We aimed to evaluate the disease and molecular characteristics of patients with early-onset CRC (40-49 years of age) and compare them with those of very early-onset CRC (&lt;40 years of age). METHODS: A retrospective cross-sectional study was performed using our electronic pathology database. All patients diagnosed with CRC between January 2012 and September 2018 were included. Data regarding patient demographics, comorbid conditions and patient presentation was noted. We also noted information regarding the location, staging and molecular features of CRC. RESULTS: A total of 627 patients with CRC were identified. Out of these, 117 (18.6%) were younger than 50 years of age (early-onset CRC). From patients &lt; 50 years of age, 74 (63.2%) had early-onset CRC (40-49 years of age) and 36.8% of patients had very early-onset (&lt;40 years of age). The mean age was 45.4 in those between 40-49 years of age and 33.5 in those &lt; 40 years of age. The most common complaint in early-onset CRC was rectal bleeding (44.6%), while abdominal pain was the most common (39.5%) complaint in the very-early onset CRC group. There were no differences in stage of CRC among both groups. Microsatellite instability (MSI) was more common in patients with very early-onset CRC (40.7 vs 13.6%, P-value = 0.009) as compared to those with early onset CRC. Other clinical and molecular features of patients with very-early onset CRC are summarized in Table 1. CONCLUSION: There are unique clinical characteristics and molecular features in patients with very-early onset CRC. Our study shows that patients very early-onset CRC have increased MSI. Although our study limitations include a small sample size and an experience from a single center, our findings suggest that further understanding of molecular features in patients with very early-onset CRC is needed to improve diagnosis and management of CRC in this age group.

Personalizing the Prediction of Colorectal Cancer Prognosis by Incorporating Comorbidities and Functional Status into Prognostic Nomograms.

Despite consistent evidence that comorbidities and functional status (FS) are strong prognostic factors for colorectal cancer (CRC) patients, these important characteristics are not considered in prognostic nomograms. We assessed to what extent incorporating these characteristics into prognostic models enhances prediction of CRC prognosis. CRC patients diagnosed in 2003–2014 who were recruited into a population-based study in Germany and followed over a median time of 4.7 years were randomized into training (n = 1608) and validation sets (n = 1071). In the training set, Cox models with predefined variables (age, sex, stage, tumor location, comorbidity scores, and FS) were used to construct nomograms for relevant survival outcomes. The performance of the nomograms, compared to models without comorbidity and FS, was evaluated in the validation set using concordance index (C-index). The C-indexes of the nomograms for overall and disease-free survival in the validation set were 0.768 and 0.737, which were substantially higher than those of models including tumor stage only (0.707 and 0.701) or models including stage, age, sex, and tumor location (0.749 and 0.718). The nomograms enabled significant risk stratification within all stages including stage IV. Our study suggests that incorporating comorbidities and FS into prognostic nomograms could substantially enhance prediction of CRC prognosis.

Prognostic and predictive role of DNA mismatch repair status in stage II-III colorectal cancer: A systematic review and meta-analysis.

DNA mismatch repair (MMR) status was considered to be a potential prognostic factor for colorectal cancer (CRC) but with conflicting reports, and varied in terms of TNM stages. Its relationship with prognosis in stage II-III CRC had not yet been systematically established. Therefore, we retrieved eligible studies published through May 2019, and screened out 51 studies that reported survival data (overall survival [OS] and/or disease-free survival [DFS]) in 28 331 CRC patients at stage II-III, totally 16.4% of whom were characterized as deficient MMR (dMMR). Significant associations of dMMR status were observed with longer OS (Hazard Ratio [HR] = 0.74, 95% CI: 0.68-0.82; P < .001), as well as DFS (HR = 0.67, 95% CI: 0.59-0.75, P < .001). However, dMMR patients received no statistically significant benefit from fluoropyrimidine-based treatment for either OS (HR = 0.84, 95%CI: 0.60-1.17; P = .31) or DFS (HR = 0.83, 95%CI: 0.60-1.15; P = .27), compared with that in proficient MMR (pMMR) patients for both OS (HR = 0.55, 95% CI: 0.43-0.71; P < .001) and DFS (HR = 0.60, 95% CI: 0.50-0.73; P < .001). Our analysis indicate that dMMR CRC patients at stage II-III had higher OS and DFS than pMMR ones, and fluoropyrimidine-based chemotherapy could improve survival in pMMR patients rather than dMMR ones.

Sentinel Lymph Node Biopsy in Colon Cancer: an Institutional Experience.

Lymph node staging is a major prognostic factor in colorectal cancer and remains to be the most important criterion for selecting patients for adjuvant therapy. The standard approach for lymph node evaluation is based on manual dissection and histological evaluation of HE-stained slides. For stage III disease (node positive), adjuvant chemotherapy increases the survival rate, while in node-negative stage II disease, in most cases, the chemotherapy is contraindicated due to increased morbidity without real benefit. Up to 30% of patients with node-negative colon cancer staged by standard pathologic techniques ultimately suffer disease recurrence and tumour-related mortality following potentially curative primary resection. Variations in outcome among patients with node-negative early-stage disease may reflect inadequate nodal resection and inaccuracies of pathologic staging. Hence, an accurate pN stage becomes essential. It is seen that classic pathological exam sometimes fails to identify lymph node micrometastases or isolated tumour cells, which might explain local or distant relapses in stage II patients. Sentinel lymph node study has the potential to detect micrometastases and lead to upstaging the disease which is crucial for planning adjuvant therapy and follow-up in these patients. In our study, we carried out SLNB in 40 clinically stage II patients operated for colon cancer. We used peritumoural injection of dye at the time of surgery to detect SLN(s) and analysed them using both microsectioning and immunohistochemical (IHC) staining. Our results show that SLNB can improve the accuracy of pTNM staging.

Role of extracellular LncRNA-SNHG14/miRNA-3940-5p/NAP12 mRNA in colorectal cancer

Background We aim to identify and analyze the expression of dyregulated RNAs in colorectal cancer (CRC). Methods We selected a panel of RNAs specific to CRC composed of Nucleosome Assembly Protein 1 Like 2 (NAP1L2) mRNA, LNCRNA SNHG14 small nucleolar RNA host gene 14 (LNCRNA SNHG14) and homo sapiens microRNA-3940-5p(hsa-miRNA-3940-5p) from genetic and epigenetic databases. Validation of the chosen RNAs was achieved by real time quantitative PCR in sera of patients with CRC, versus controls groups (benign lesions and healthy individual). Results We found that LLNCRNA SNHG14, hsa-miRNA-3940-5p and NAP1L2 mRNA had an excellent performance characteristics and more superior than CEA, and CA19.9 for differentiating CRC from controls. Combined expression of lncRNA SNHG14- hsa-miR-3940-5p and NAP1L2 mRNA had reached 100% sensitivity with accuracy 93%. Interestingly, serum hsa-miRNA-3940-5p could be an independent prognostic factor in CRC. Conclusion The extracellular lncRNA SNHG14- hsa-miR-3940-5p - NAP1L2 mRNA may aid in CRC management. KEY MESSAGES The extracellular RNAs provide a potential class of noninvasive biomarkers with high specificity, accuracy and stability for detection of CRC. We used insilico data analysis followed by qPCR for detection of differential NAP1L2 gene expression with the selected epigenetic regulators. Our data presented interesting biomarker panel (NAP1L2 gene, lncRNA-SNHG14 and hsa-miR-3940-5p) that may be potential for CRC diagnosis and prognosis.

EXOSC5 as a Novel Prognostic Marker Promotes Proliferation of Colorectal Cancer via Activating the ERK and AKT Pathways.

Background and Objective: Exosome component 5 (EXOSC5) is a novel cancer-related gene that is aberrantly expressed in various malignances. However, the molecular mechanism and biological role of EXOSC5 have not been explored in colorectal cancer (CRC). In this study, we investigated the functions and mechanisms by which EXOSC5 promotes the progression of CRC.Methods: EXOSC5 expressions in CRC cell lines and paired CRC and adjacent normal tissues were measured via quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry (IHC). In vitro experiments including colony formation, Cell Counting Kit-8 (CCK-8), and flow cytometry and in vivo tumorigenesis assay were performed to explore the effects of EXOSC5 on growth of CRC. The impacts of EXOSC5 on ERK and Akt signaling pathways were measured by Western blot.Results: The mRNA and protein expression levels of EXOSC5 were up-regulated in CRC as compared to adjacent normal tissues. IHC analysis indicated that high EXOSC5 level was positively associated with poor prognosis. EXOSC5 overexpression facilitated the growth of CRC cells, while EXOSC5 knockdown led to decreased proliferation, G1/S phase transition arrest. The oncogenic functions of EXOSC5 were associated with activation of the ERK and Akt pathways in CRC.Conclusion: EXOSC5 is overexpressed in CRC and promotes CRC growth partly through activation of ERK and Akt signaling pathways. Accordingly, EXOSC5 may be a novel oncogene, and acts as a therapeutic target, or prognostic factor for CRC.

Eukaryotic elongation factor-2 kinase expression is an independent prognostic factor in colorectal cancer

BackgroundPrognostication of patients with colorectal cancer (CRC) currently relies on tumor-node-metastasis (TNM) staging but clinical outcomes of patients of the same histoclinical stage are heterogeneous. It is therefore imperative to devise novel molecular tests to stratify CRC patients. Our previous work demonstrated that eukaryotic elongation factor-2 kinase (EEF2K) is a tumor suppressor in CRC. Herein, we investigated EEF2K expression in CRC and determined its relationship with clinicopathological parameters.MethodsQuantitative RT-PCR and Westerns blots were used to examine EEF2K expression in primary tumor and the adjacent non-tumor tissues of CRC patients (n = 20). Kaplan-Meier curves and Cox regression analysis were used to assess the association between clinical outcomes of CRC patients and EEF2K protein expression determined by immunohistochemistry on tissue microarray (n = 151).ResultsEEF2K was significantly downregulated at both mRNA and protein levels in tumors of CRC patients. Univariate Cox regression analysis revealed that CRC patients with high tumor grade, advanced TNM staging and low EEF2K expression were associated with worse overall survival. Multivariate analysis further demonstrated that low EEF2K expression was an independent factor for predicting poorer overall survival in CRC patients (p = 0.014; Hazard ratio = 2.951; 95% confidence interval: 1.240–7.024). The 5-year survival rate was 82.8% in the EEF2K-high-expression group versus 63.9% in the EEF2K-low-expression group (p = 0.0118). The association of overall survival with EEF2K expression in CRC patients was verified in The Cancer Genome Atlas (TCGA) cohort.ConclusionsEEF2K is downregulated in CRC and its expression can be employed as a prognostic marker for CRC patients independent of TNM staging.

Dystrophin Controls Exosome Secretion and Promotes Drug Resistance via Protein-Protein Interaction with Rab GTPase 3C in Colorectal Carcinoma

Background: RAB GTPases is involved in membrane trafficking (vesicle formation) and cell motility. Recently, exocytotic RABs has been noted that the exocytosis by RABs is correlated with drug resistance and immune response in tumorigenesis. However, the molecular mechanisms of exocytotic RABs in colorectal tumorigenicity remain unknown. Methods: Established RAB3C-based proteomics datasets and mass spectrometry analyses and found dystrophin (DMD) is upregulated in RAB3C ectopically overexpressed colon cancer cell lines. High DMD expression levels were found correlated with poor survival in colorectal cancer patient cohorts. Findings: We further found that DMD is a rare mutant event in colorectal clinical cohort by next generation sequencing analysis. Our results showed that DMD could be stabilized by RAB3C through protein-protein interaction. Besides, our results revealed RAB3C co-localized with dystrophin complex by immunohistochemistry staining analysis. Merged DMD with RAB3C serves as a significant independent prognostic factor in colorectal cancer and is associated with several clinical parameters. In addition, dystrophin complex decreased cell membrane integrity and altered calcium channel activity for exocytosis. Interpretation: DMD is a new functional binding protein for RAB3C that affected colorectal carcinogenesis. These findings suggest a new therapeutic strategy for targeting cancer-specific protein-protein interactions in the treatment patients with colorectal cancer. Funding Statement: This study is supported by Academia Sinica grants AS-SUMMIT-108 to Michael Hsiao. Declaration of Interests: The authors have no competing financial interests to declare. Ethics Approval Statement: The studied tissues were retrieved from the Department of Pathology, Taipei Municipal Wan Fang Hospital (Taipei, Taiwan) with Institutional Review Board approval (TMU-IRB 99049).

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma.

BackgroundSMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.MethodsWe retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.ResultsA loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancer-specific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).ConclusionsWe confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

Budget Impact Analysis of Molecular Lymph Node Staging Versus Conventional Histopathology Staging in Colorectal Carcinoma.

BackgroundThe presence of lymph node (LN) metastasis is a critical prognostic factor in colorectal cancer (CRC) patients and is also an indicator for adjuvant chemotherapy. The gold standard (GS) technique for LN diagnosis and staging is based on the analysis of haematoxylin and eosin (H&E)-stained slides, but its sensitivity is low. As a result, patients may not be properly diagnosed and some may have local recurrence or distant metastases after curative-intent surgery. Many of these diagnostic and treatment problems could be avoided if the one-step nucleic acid amplification assay (OSNA) was used rather than the GS technique. OSNA is a fast, automated, standardised, highly sensitive, quantitative technique for detecting LN metastases.ObjectivesThe aim of this study was to assess the budget impact of introducing OSNA LN analysis in early-stage CRC patients in the Spanish National Health System (NHS).MethodsA budget impact analysis comparing two scenarios (GS vs. OSNA) was developed within the Spanish NHS framework over a 3-year time frame (2017–2019). The patient population consisted of newly diagnosed CRC patients undergoing surgical treatment, and the following costs were included: initial surgery, pathological diagnosis, staging, follow-up expenses, systemic treatment and surgery after recurrence. One- and two-way sensitivity analyses were performed.ResultsUsing OSNA instead of the GS would have saved €1,509,182, €6,854,501 and €10,814,082 during the first, second and third years of the analysis, respectively, because patients incur additional costs in later years, leading to savings of more than €19 million for the NHS over the 3-year time horizon.ConclusionsIntroducing OSNA in CRC LN analysis may represent not only an economic benefit for the NHS but also a clinical benefit for CRC patients since a more accurate staging could be performed, thus avoiding unnecessary treatments.Electronic supplementary materialThe online version of this article (10.1007/s40258-019-00482-7) contains supplementary material, which is available to authorized users.

Optimizing cut-offs for high neutrophil-to-lymphocyte ratio as poor survival prognostic factor in colorectal cancer.

e15111 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Needing to use all the possible tools for an accurate diagnosis and early treatment. Neutrophil-to-lymphocyte ratio (NLR) has been associated as poor prognostic factor in OS and PFS in CRC. There is no data that support this statement in Latin America. It is of a special utility in our country the detection of a simple and reproducible prognostic biomarker that guides the use of more advanced tests. Our objective was to explore the factors associated with OS in the local-locally advanced and metastatic settings. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We divided our population into two groups: Local-locally advanced (L-LA) (516 pts) and debut metastatic- recurrence (M-R) (108 pts). We performed a ROC curve analysis to determine an appropriate cut-off value for NLR in both groups (L-LA:NLR ≥3, M-R:NLR ≥5). A univariate survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: Pts with high NLR had significantly shorter OS in L-LA [HR, 12.1; 95% CI,5.019-29.211; p &lt; 0.001] M-R [HR, 5.382; 95% CI,2.835-10.217; p &lt; 0.001] than pts with low NLR. In the multivariate model, NLR retained a significant association with OS in both groups. Cox regression demonstrated that in L-LA setting sex, histologic grade and lymph node involvement; and in M-R setting sidedness, histologic grade, LVI and metastasectomy performed were independently risk factors for a shorter OS. Conclusions: High NLR is associated with poor prognosis (with our cut-offs L-LA:NLR ≥3, M-R:NLR ≥5). There are other variables to be considered that affect the OS, as: sex, histologic grade and lymph node involvement, sidedness, histologic grade, LVI and metastasectomy performed.

Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.

e15115 Background: CDX2 (Caudal Type Homeobox 2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumourogenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (colorectal cancer) and its association with prognosis. Methods: We performed CDX2 staining by Immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done by semi-quantitative method. Results: 286 patients were registered during study period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33 (30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33 (30%) patients had stage II disease, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 expression was significantly associated with advanced stage, rectal site, poor grade of differentiation, and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative patients compared to 67% CDX2 positive (P=0.009), while OS (overall survival) at 2 years was 46% for CDX2 negative versus 77% for positive patients (p=0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as a poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.

MicroRNA-124 regulates TRAF6 expression and functions as an independent prognostic factor in colorectal cancer.

An increasing number of studies have confirmed that miR-124 exhibits a suppressive role in glioblastoma, cervical cancer and breast cancer; however, the function of miR-124 in colorectal cancer (CRC) has not been completely elucidated. In the present study, miR-124 expression was confirmed by reverse transcription-quantitative PCR in 80 colorectal tissues and para-cancerous tissues. The influence of altered miR-124 expression was analyzed by statistical approaches including Cox multivariate regression analysis and the Kaplan-Meier method, and the target genes of miR-124 were confirmed by luciferase reporter assays. Immunohistochemical techniques were also performed in order to measure the expression levels of target proteins. miR-124 expression was observed to be decreased in colorectal tissue samples, and this phenomenon was correlated with adverse clinical indicators and poor patient survival time. Luciferase reporter assays indicated that miR-124 directly regulated TNF receptor associated factor 6 (TRAF6) 3′-untranslated region (UTR). Hence, it was proposed that miR-124 dysregulation may negatively influence the expression of TRAF6 and therefore serve as a biomarker of epithelial-mesenchymal transition in CRC tissues. In summary, the present study demonstrated that miR-124 regulates the expression of TRAF6, and may potentially function as an independent prognostic factor and therapeutic target in patients with CRC.

High expression of MMP19 is associated with poor prognosis in patients with colorectal cancer

BackgroundMatrix metalloproteinase 19 (MMP19) is a member of zinc-dependent endopeptidases, which have been involved in various physiological and pathological processes. Its expression has been demonstrated in some types of cancers, but the clinical significance of MMP19 in colorectal cancer (CRC) has not been reported. Thus, we aimed to analyze the clinical significance of MMP19 in CRC in present study.MethodsThe expression of MMP19 was first explored in The Cancer Genome Atlas (TCGA) cohort, and then validated in the GSE39582 cohort and our own database. Clinicopathological features and survival rate were also investigated.ResultsMMP19 was found to be a predictor for overall survival (OS) in both univariate (hazard ratio [HR]: 1.449, 95% confidence interval [CI]: 1.108–1.893, P = 0.007) and multivariate survival analyses (HR: 1.401, 95% CI: 1.036–1.894, P = 0.028) in the TCGA database. MMP19 was further validated as an independent factor for recurrence free survival in the GSE39582 database by both univariate analysis (HR: 2.061, 95%CI: 1.454–2.921, P < 0.001) and multivariate analysis (HR = 1.470, 95% CI: 1.025–2.215, P = 0.032). In an in-house cohort, MMP19 was significantly upregulated in CRC tissues when compared with their adjacent normal controls (P < 0.001). Ectopic MMP19 expression was positively associated with lymph node metastases (P = 0.029), intramural vascular invasion (P = 0.015) and serum carcinoembryonic antigen levels (P = 0.045). High MMP19 expression correlated with a shorter OS (HR = 5.595; 95% CI: 2.573–12.164; P < 0.001) and disease free survival (HR = 4.699; 95% CI: 2.461–8.974; P < 0.001) in multivariate cox regression analysis.ConclusionsExpression of MMP19 was upregulated in CRC. High expression of MMP19 was determined to be an independent and poor prognostic factor in CRC. These results suggest that MMP19 may be a good biomarker for CRC.

Long non-coding RNA IQCJ-SCHIP1 antisense RNA 1 is downregulated in colorectal cancer and inhibits cell proliferation.

IQCJ-SCHIP1 antisense RNA 1 (IQCJ-SCHIP1-AS1) was a functional novel long non-coding RNA (lncRNA) revealed by our previous expression profile. In this study, we aim to investigate its clinical relevance and biological significance in colorectal cancer (CRC). We measured the expression levels of IQCJ-SCHIP1-AS1 in 86 paired CRC tissues using quantitative RT-PCR assay, and then analyzed its association with patient prognoses. Moreover, gain-of-function and loss-of-function studies were performed to examine the biological functions of IQCJ-SCHIP1-AS1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to elucidate potential mechanisms of IQCJ-SCHIP1-AS1 in CRC. More than 2-fold decreased expression of IQCJ-SCHIP1-AS1 was found in half of CRC tissues (53.5%, 46/86). IQCJ-SCHIP1-AS1 down-regulation was correlated with poor differentiation (P=0.025), advanced depth of tumor (P=0.022), lymphatic invasion (P=0.010), advanced tumor stage (P=0.006), and poor prognosis (P=0.0027) in CRC patients. The Cox proportional hazards model demonstrated that IQCJ-SCHIP1-AS1 expression was an independent prognostic factor for CRC (HR =0.247, 95% CI: 0.081-0.752, P=0.014). Moreover, knockdown of IQCJ-SCHIP1-AS1 promoted CRC cell proliferation through increasing cell cycle progression and impairing cell apoptosis. Additionally, bioinformatics analysis showed that differential expression genes in IQCJ-SCHIP1-AS1-depleted CRC cells were enriched in the pathways of cell cycle, DNA replication, and p53. Our results demonstrate that IQCJ-SCHIP1-AS1 has an indicative tumor suppressor role and appears to be a potential prognostic factor in CRC for the first time.

The Impact of Muscle and Adipose Tissue on Long-term Survival in Patients With Stage I to III Colorectal Cancer.

Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer. This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival. All patients were seen in a tertiary care cancer center. Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included. Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity. Primary outcome measures were overall, recurrence-free, and cancer-specific survival. In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model. The limitations of this study are inherent in retrospective observational studies. Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

Random forest prognostic factor in colorectal cancer

In developing countries such as Indonesia, colorectal cancer cases in women are the third largest after breast cancer and cervical cancer, whereas, in men, cancer ranks second after lung cancer, followed by the third is prostate cancer. This study aims to determine the factors that affect the survival of colorectal cancer patients in the city of Makassar, Indonesia. The data used in this study including colon cancer patients diagnosed first in 2012 in 4 hospitals in Makassar City and observed survival until 2015. Predictor variables consisted of comorbidity, stage of cancer, age, treatment status, the location of cancer, sex, and history of metastasis of patients with colorectal cancer. The samples used in this study were as many as 38 cancer patients. In this study, we are using random forest which is an algorithm used in data classification through tree merging by training on sample data. Random Forest also an ensemble method consisting of several decision trees as classifiers. In a nutshell, the accuracy of this models can be justified by the value of classification by Area Under Curve (AUC) equal to 50%. Moreover, the most influential variable on the survival of colorectal cancer patient is a history of metastasis of colorectal cancer patient, cancer location and gender respectively.

PROGNOSTIC MARKERS IN IMMUNOHISTOCHEMICAL DIAGNOSIS OF METASTASES OF COLORECTAL PHENOTYPE CARCINOMA OF UNKNOWN PRIMARY

Most metastases of cancers of unknown primary (80% -85%) are known as having unfavourable prognostic variants due to their large extant and low susceptibility to the therapy. Studies of prognostic immunohistochemical markers will provide an opportunity to understand the biological features of the rapid dissemination of individual colorectal phenotypes. In recent decades, p53 and Ki-67, the most popular antibodies have been investigated as prognostic factors for colorectal cancer. The p53 protein is a regulatory protein that is at the crossroads of cell division and cell death. The goal of this study is to explore the expression features of prognostic immunohistochemical markers Ki-67, p53, β-catenin, AMACR (p503s), HER2-new in carcinomas of unknown primary of the colorectal phenotype compared with primary tumours of the colon, to improve diagnostic algorithms. Materials and methods. A study of biopsy material taken from 37 patients aged 28 to 81 years (mean 58.46 ± 12.28; median 58), group 1, with metastases without primary localization was carried out; the immunohistochemical investigation revealed adenocarcinomas of the colorectal phenotype CK20 + / CDX2 + / CK7; the investigation of postoperative material in 41 patients aged 27 to 76 years (mean 60.56 ± 12.81; median 64), group 2, revealed primary colon tumour. Results. Positive focal expression of p53 was found in the colorectal cancers of the proximal sections (located to the right), it is they that more often have microsatellite instability, compared to distal carcinomas. Amplification of the Her-2-new gene (expression at the level of 2+ and 3+) was found in 35% (13 of 37) of metastasis of colorectal cancers, and in almost 15% (6 of 41) of primary colon adenocarcinomas that suggests the appropriateness in applying targeted therapy.Conclusions. Nuclear translocation of β-catenin, positive “focal” expression of p53 and amplification of the Her-2-new gene are statistically significantly more common in colorectal phenotype metastases compared with primary colon adenocarcinomas (all р&gt; 0.05).

Dystrophin Promotes Colorectal Carcinoma Metastasis and Exosome Secretion via Protein‐Protein Interaction with Rab GTPase 3C

RAB GTPases is involved in membrane trafficking (vesicle formation) and cell motility. Recently, exocytotic RABs has been noted that the exocytosis by RABs is correlated with drug resistance and immune response in tumorigenesis. However, the molecular mechanisms of exocytotic RABs in colorectal tumorigenicity remain unknown. RAB GTPase 3C (RAB3C) has been identified as the key component for exosome formation and exocytosis. In clinical colorectal carcinoma patient cohort, high RAB3C expression maintained its independent prognostic significance for both overall survival and disease‐free survival. We further established RAB3C‐based proteomics datasets and mass spectrometry analyses and found dystrophin (DMD) is upregulated in RAB3C ectopically overexpressed colon cancer cell lines. High DMD expression levels were found correlated with poor survival in colorectal cancer patient cohorts. Moreover, Dystrophin‐complex components including dystrobrevin (DTNA) and syntrophin (SNTA1/SNTB1) also showed the same prognosis trends in colorectal cancer patients. We further found that DMD is a rare mutant event in colorectal clinical cohort by next generation sequencing analysis. Our results showed that DMD could be stabilized by RAB3C through protein‐protein interaction. Besides, our results revealed RAB3C co‐localized with dystrophin complex by immunohistochemistry staining analysis. Merged DMD with RAB3C serves as a significant independent prognostic factor in colorectal cancer and is associated with several clinical parameters. In addition, dystrophin complex decreased cell membrane integrity and altered calcium channel activity for exocytosis. In summary, our results identified DMD is a new functional binding protein for RAB3C that affected colorectal carcinogenesis. These findings suggest a new therapeutic strategy for targeting cancer‐specific protein‐protein interactions in the treatment patients with colorectal cancer.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.