Factor In Colorectal Cancer Patients Research Articles

The impact of primary tumour location in patients undergoing hepatic resection for colorectal liver metastasis

BackgroundPrimary tumour location has long been debated as a prognostic factor in colorectal cancer patients with liver metastases (CRLM) undergoing liver resection. This retrospective study was conducted to clarify the prognostic value of tumour location after radical hepatectomy for CRLM and its underlying causes. MethodsWe retrospectively analysed clinical data from 420 patients with CRLM whom underwent liver resection between January 2002 and December 2015. Right-sided (RS) tumours include tumours located in the cecum, ascending colon, and transverse colon, and left-sided (LS) tumours include those located in the splenic flexure, descending colon, sigmoid colon, and rectum. ResultsBoth overall survival (OS) and disease-free survival (DFS) were similar between patients with RS and LS primary tumours (5-year OS: 46.5% vs 38.3%, P = 0.699; 5-year DFS: 29.1% vs 22.4%, P = 0.536). Specifically, RAS mutation rate was significantly higher in patients with RS tumours (P = 0.007). Subgroup analysis showed that the RAS mutation on the LS and RS tumours have different prognostic impact for CRLM patients on long-term survival after hepatic resection (RS, OS: P = 0.437, DFS: P = 0.471; LS, OS: P < 0.001, DFS: P = 0.002). The multivariable analysis showed that RAS mutant is an independent factor influencing OS in patients with LS primary tumour only. ConclusionsThe site of the primary tumour has no significant impact on the long-term survival in patients with CRLM undergoing radical surgery. However, prognostic value of RAS status differs depending on the site of the primary tumour.

TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway

BackgroundAberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. The purpose of this study is to investigate the clinical significance and biological roles of TFAP2C in colorectal cancer (CRC).MethodsTFAP2C expression was evaluated by real-time PCR, Western blot and immunohistochemistry (IHC) respectively in clinical CRC tissues. Statistical analysis was performed to explore the correlation between TFAP2C expression and clinicopathological features, and overall and progression-free survival in CRC patients. In vitro and in vivo assays were performed to assess the biological roles of TFAP2C in CRC cells. Western blot, luciferase and Chromatin immunoprecipitation (ChIP) assays were used to identify the underlying pathway mediating the biological roles of TFAP2C in CRC.ResultsTFAP2C is robustly upregulated in CRC tissues and cells, and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients. Furthermore, upregulating TFAP2C enhances spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and reduces the apoptosis induced by 5-fluorouracil in colorectal cancer cells in vitro, and promotes stemness and chemoresistance of CRC cells in vivo; while silencing TFAP2C yields an opposite effect. Importantly, downregulation of TFAP2C dramatically restores chemotherapeutic sensitivity of CRC cells to 5-FU in vivo. Our results further demonstrate that TFAP2C promotes stemness and chemoresistance of CRC cells to 5-FU by inhibiting Hippo signaling via transcriptionally upregulating ROCK1 and ROCK2 in CRC cells.ConclusionOur findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients.

Composition and Concentration of Serum Fatty Acids of Phospholipids Depend on Tumour Location and Disease Progression in Colorectal Patients.

SummaryBackgroundPolyunsaturated fatty acids (PUFAs) play a role in the development/progression of colon cancer. The aim of the study was to assess the relation between serum phospholipids PUFAs, colorectal tumour localization and disease progression.MethodsA total of 67 patients (18 with proximal colon, 17 with distal colon and 32 with rectal tumour localization) as well as 16 controls were studied. One year after surgery, 33 patients had disease progression. Serum levels of C16:1(n-7), C18:1(n-9), C18:3(n-3), C20:5(n-3), C22:6(n- 3), C18:2(n-6), C20:2(n-6), C20:4(n-6) fatty acids of se - rum phospholipids were quantitatively measured before surgery by gas-chromatography.ResultsSignificantly higher mean value of C18:2, as compared to control, has been noted only for patients with proximal (p<0.05) and distal tumour (p<0.03) localization. The lower mean level of C20:5 and unsaturation index (UI) were observed in colorectal cancer patients regardless the tumour localization, but the statistical difference was noted only for patients with proximal tumours (p<0.05, p<0.03). In patients with proximal tumours, significantly lower mean level of C20:4 and UI were noted in patients with disease progression, as compared to patients with proximal tumours without disease progression (p<0.05).ConclusionThe evaluation of PUFAs as a risk/prognostic factor in colorectal cancer patients should take into account tumour localization as a dependent variable.

Upregulation of lncRNA BANCR associated with the lymph node metastasis and poor prognosis in colorectal cancer

BackgroundGrowing evidence has supported that long non-coding RNAs (lncRNAs) could play vital roles in the development, progression, and prognosis of colorectal cancer (CRC). However, little is known about the clinical significance of BRAF-activated non-coding RNA (BANCR) in CRC. The aim of this study is to explore the clinical value of lncRNA BANCR in CRC patients.MethodsThe expression of lncRNA BANCR was measured in 106 CRC tissues and 65 adjacent normal tissues using the quantitative real-time PCR.ResultsThe study showed that lncRNA BANCR was highly expressed in CRC tissues compared with adjacent normal tissues (P < 0.001). In addition, high expression of lncRNA BANCR was positively correlated with the lymph node metastasis (P < 0.001). Kaplan–Meier analysis showed that patients with high lncRNA BANCR expression had a shorter overall survival (OS) compared with the low lncRNA BANCR expression group (P = 0.001). Interestingly, for the group of patients with the lymph node metastasis, we found the similar result that high lncRNA BANCR expression was related to poor OS (P = 0.004). Furthermore, the multivariate Cox regression model analysis indicated that high expression of lncRNA BANCR was an independent poor prognostic factor in CRC patients (HR 2.24, 95% CI 1.22–4.16, P = 0.009).ConclusionsUpregulation of lncRNA BANCR may be associated with the lymph node metastasis and poor survival of CRC. LncRNA BANCR could be served as a novel and useful biomarker for CRC lymph node metastasis and prognosis.

Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer

A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203, a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203-transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.

Abstract 81: E2F4/p107 complex regulates chemotherapy resistance in human colorectal cancer stem cells

Abstract Most cancer patients experience disease progression despite one or multiple lines of treatment with cytotoxic chemotherapy. Evidence from human trials and in vivo experiments on patient-derived xenograft (PDX) tumor lines indicates that cancer stem cells (CSCs) can survive chemotherapy treatment. However, the mechanism of chemotherapy resistance in CSCs is not fully elucidated. To identify new mechanisms of the drug-resistance in colorectal cancer, we used gene-expression microarrays to examine the gene expression profile of CSCs and non-CSCs in four human PDX models of colorectal cancer, both before-and-after treatment with cytotoxic chemotherapy. The gene-expression data were analyzed using Independent Component Analysis (ICA) followed by Transcription Factor Target Genes (TFTG) enrichment analysis, which identified the transcription factor E2F4 as a candidate regulator of chemotherapy resistance in colorectal CSCs. E2F4 was predominantly expressed in the CSC-enriched cell population (CD44+/CD166+ human colorectal cancer cells). E2F4 knock-down sensitizes cancer cells to chemotherapy in three different PDX tumors as well as HT29 cells. Co-immunoprecipitation experiments showed that E2F4 forms a complex with p107 and DP-1, which also contributed to the chemotherapy resistance. Simultaneous knock-down of both E2F4 and p107 enhanced chemotherapy sensitivity more than E2F4 knock-down alone. In normal intestinal crypt cells E2F4 was dispensable for chemotherapy resistance. ChIP-seq and RNA-seq experiments revealed that LDHA is a key downstream target of E2F4. LDHA knock-down sensitizes cancer cells to chemotherapy. High LDHA expression in tumor tissues was an independent poor prognostic factor in colorectal cancer patients (n=466), as well as in non-small cell lung cancer (n=1,926) and breast cancer (n=3,554). Thus, the E2F4/p107-LDHA pathway represents a novel therapeutic target to overcome chemotherapy resistance in CSCs. Citation Format: Junichi Matsubara, Yong F. Li, Piero Dalerba, Debashis Sahoo, Taichi Isobe, Russ B. Altman, Michael F. Clarke. E2F4/p107 complex regulates chemotherapy resistance in human colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2017-81

The research progress of physical activity in colorectal cancer patients

The aim of this review is to realize the significance of physical activity for colorectal cancer survivors, collect the common tools to assess colorectal cancer patients′ physical activity, understand the current status and its influencing factors of colorectal cancer patients′ physical activity as a reference to Chinese relevant research and provide a basis for carrying out medical or nursing intervention. Key words: Intestinal Neoplasms; Rectal Neoplasms; Colonic Neoplasms; Physical activity; Review

Oncologic and surgical outcomes in colorectal cancer patients with liver cirrhosis: A propensity-matched study.

The management of colorectal cancer in patients with liver cirrhosis requires a thorough understanding of both diseases. This study evaluated the effect of liver cirrhosis on oncologic and surgical outcomes and prognostic factors in colorectal cancer patients. Fifty-five consecutive colorectal cancer patients with liver cirrhosis underwent colorectal resection (LC group). Using a prospectively maintained database, these patients were matched 1:4 using propensity scoring with R programming language, package "MatchIt" and "optmatch" by sex, age, cancer location, and tumor stage with 220 patients without liver cirrhosis (non-LC group), resulting in 275 patients. The 5-year overall survival (OS) was significantly worse in the LC group than in the non-LC group (46.7% vs. 76.2% respectively, P < 0.001); however, the 5-year proportion of recurrence free (PRF) rates were similar (73.1% vs. 84.5% respectively, P = 0.094). On multivariate analysis of the LC group, tumor-node-metastasis (TNM) stage ≥III disease, venous invasion, and a model for end-stage liver disease plus serum sodium (MELD-Na) score >10 were prognostic factors for OS. However, the OS was not different between the LC group with MELD-Na score ≤10 and the non-LC group (5-year OS rate, TNM stage ≤II, 85.7 vs 89.5%, p = 0.356; TNM stage ≥III, 41.1 vs 66.2%, p = 0.061). Colorectal cancer patients with liver cirrhosis have poorer OS compared to those without liver cirrhosis; however, the PRF rates are similar. It might be due to the mortality from the liver, and surgical treatment should be actively considered for patients with MELD-Na score <10.

P62/sequestosome 1 in human colorectal carcinoma as a potent prognostic predictor associated with cell proliferation.

p62/sequestosome 1 (p62) is a multi‐domain protein that functions as a receptor for ubiquitinated targets in the selective autophagy and serves as a scaffold in various signaling cascades. p62 have been reported to be up‐regulated in several human malignancies, but the biological roles and significance of p62 are still poorly understood in colorectal carcinoma. We immunohistochemically evaluated p62 in 118 colorectal adenocarcinoma and 28 colorectal adenoma cases. We used four colon carcinoma cells (HCT8, HT29, COLO320, and SW480) in the in vitro studies. p62 immunoreactivity was detected in 11% of colorectal adenoma cases and 31% of adenocarcinoma cases, while it was negligible in the normal epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis, and it turned out to be an independent adverse prognostic factor in colorectal cancer patients. Following in vitro studies revealed that HCT8 and HT29 cells transfected with p62‐specific siRNA showed significantly decreased cell proliferation activity, whereas COLO320 and SW480 cells transfected with p62 expression plasmid showed significantly increased cell proliferation activity. The p62‐mediated cell proliferation was not associated with the autophagy activity. These findings suggest that p62 promotes the cell proliferation mainly as a scaffold protein, and that the p62 status is a potent prognostic factor in colorectal carcinoma patients.

Clinical Significance of 5-Fluorouracil Chemosensitivity Testing in Patients with Colorectal Cancer.

To evaluate whether the results of chemosensitivity testing were associated with prognosis of colorectal cancer patients after adjuvant 5-fluorouracil (FU)/ leucovorin chemotherapy. Eighty-nine patients who received 5-FU/leucovorin adjuvant chemotherapy for colorectal cancer were enrolled. Chemosensitivity tests were performed and tumor growth inhibition rate was calculated using the MTT (3-(4,5-dimethylthiazol-2-yl)02,5-diphenyl-2H tetrazolium bromide) assay. Fifty-one patients (57.3%) were sensitive to 5-FU according to the chemosensitivity test. After a median follow-up of 64 months, there was a significant difference between the 5-year disease-free survival rates of the chemo-sensitive and chemo-resistant groups. However, there was no significant difference in the overall 5-year survival between the chemo-sensitive and chemo-resistant groups. A positive 5-FU sensitivity test with in vitro histoculture drug response assay (HDRA) was associated with better disease-free survival. Chemosensitivity may be a prognostic factor for colorectal cancer patients undergoing adjuvant 5-FU/leucovorin chemotherapy.

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.

Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting.Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs.Results: Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration.Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. Clin Cancer Res; 23(5); 1323-33. ©2016 AACR.

The clinical value and biological function of PTTG1 in colorectal cancer

Pituitary tumor transforming gene-1 (PTTG1) has been suggested to serve as an oncogene in several types of human tumors, but little is known about the biological function of PTTG1 in colorectal cancer. PTTG1 mRNA and protein expressions in colorectal cancer tissues and cell lines were measured by qRT-PCR, western blot or immunohistochemistry. The association between PTTG1 protein expression and clinicopathological features was analyzed. The function of PTTG1 on colorectal cancer cell proliferation and metastasis were explored through MTT, colony formation, migration and invasion assays. In our results, PTTG1 mRNA and protein expressions were increased in colorectal cancer tissues and cell lines compared with normal colonic tissues and colon epithelial cell line. PTTG1 overexpression positively associated with clinical stage, T classification, N classification, M classification and differentiation. The univariate and multivariate analyses suggested PTTG1 overexpression was an independent poor prognostic factor for colorectal cancer patients. The in vitro experiments showed knocking down PTTG1 inhibited colorectal cancer growth and metastasis. In conclusion, PTTG1 is an independent prognostic factor and acts as an oncogene in colorectal cancer.

The role of sidedness, EGFR gene copy number (GCN) and EGFR promoter methylation in RAS/BRAF wild type (WT) colorectal cancer (CRC) patients receiving irinotecan/cetuximab.

628 Background: Data from randomized trials suggested that tumour sidedness could represent a prognostic and predictive factor in CRC patients. Distinctive molecular and clinical features are related to tumour sidedness, however their predictive role has not yet been clearly defined. Methods: Tumour samples from RAS/BRAF WT metastatic CRC patients treated with second-third line irinotecan-cetuximab were analised for EGFR GCN and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Results: Eighty-eightpatients were included in the study, 24/88 (27.3%) had right sided CRC(RSCC), 64/88 (72.7%) had left sided CRC(LSCC); 32/88 (36.4%) had EGFR GCN &lt; 2.12 tumour, 56/88 (63.6%) had EGFR GCN ≥ 2.12 tumour; 44/88 (50%) had EGFR promoter methylated tumour. RSCC were associated with reduced ORR (4.2% for RSCC vs 35.9% for LSCC, p:0.0030), with shorter PFS (3.0 vs 10.29 months, HR:2.74, p &lt; 0.0001) and shorter OS (8.0 vs 13.6 months, HR:2.83, p &lt; 0.0001). EGFR GCN &lt; 2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN &lt; 2.12 vs 39.3% for ≥ 2.12 tumours, p:0.0009), with shorter PFS (3.8 vs 7.0 months HR:2.15, p = 0.0010) and shorter OS (8.5 vs 14.0 months HR:2.59, p &lt; 0.0001). EGFR methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, p = 0.0001), with shorter PFS (3.0 vs 7.67 months HR:3.23, p &lt; 0.0001) and shorter OS (8.0 vs 17.0 months HR:3.57, p &lt; 0.0001). At multivariate analysis EGFR GCN and EGFR promoter methylation mantained their independent role for ORR (respectively p:0.0082 and p:0.0025), PFS (respectively Exp(b):0.40, p:0.0048 and Exp(b):4.52, p &lt; 0.0001) and OS (respectively Exp(b):0.23, p:0.0001 and Exp(b):5.58, p &lt; 0.0001). Conclusions: In our study an accurate molecular selection based on an all RAS and BRAF analisys along with EGFR GCN and EGFR promoter methylation status resulted more relevant than tumour sidedness for the prediction of clinical outcome during cetuximab/irinotecan. We then suggest that molecular selection might overcome the importance of tumour sidedness in this setting.

Overall survival of elderly metastatic colorectal cancer patients treated in second and third line by tumor site.

742 Background: The anatomical side of the colon where a tumor arises has been shown to be prognostic in patients treated with first-line therapy; patients with tumors that arise from the left side of the colon have significantly longer survival compared with patients whose tumors arise from the right side of the colon. However, there is little evidence of whether this factor is prognostic in later lines of treatment. The objective of this study was to determine the impact of tumor side on the survival of metastatic colorectal cancer patients who received second line (2L) or third line (3L) therapy. Methods: Metastatic (stage IV) colorectal cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims diagnosed 2001-2005 who received 2L (n = 921) or 3L (n = 502) therapy were included in the study. Overall survival (OS) was determined from the start of the indicated line of therapy and was estimated using the Kaplan-Meier method; statistical differences were tested using the log-rank tests. Results: The distribution of tumor sites was similar for 2L and 3L treated patients (right: 36%; left: 58%; transverse: 6%; for 2L). The median follow up time from start of therapy was 11 months (mo) for 2L and 10 mo for 3L patients. Median OS for left-sided tumors receiving 2L+ therapy was 13.6 mo (95%CI: 11.9, 14.8) compared with 8.7 mo (95%CI: 7.5, 9.9) for right-sided tumors (log-rank p &lt; 0.001). Similar results were seen in patients receiving 3L+ therapy, although the difference was of lesser magnitude. The median OS for patients with left-sided tumors was 10.8 mo (95%CI: 9.6, 12.9) compared with 7.6 mo (95%CI: 5.7, 9.4) for right-sided tumors (log-rank p = 0.002). Conclusions: These results suggest that side of tumor origin remains a prognostic factor for colorectal cancer patients treated in later lines of therapy (2L+).

Research status of tumor nodules in colorectal cancer

The formation of tumor nodules is related to lymph node metastasis, neural invasion and vascular invasion. Tumor nodule is a negative prognostic factor in colorectal cancer patients, which increases the probability of recurrence and metastasis in patients with colorectal cancer. The prognostic value of tumor nodules in the lymph node metastasis is greater than the seventh edition of tumor nodules staging method, which provides a more accurate basis for the clinical treatment. Key words: Colorectal neoplasms; Prognosis; Tumor nodules

FOXM1 and FOXQ1 Are Promising Prognostic Biomarkers and Novel Targets of Tumor-Suppressive miR-342 in Human Colorectal Cancer

Colorectal cancer ranks as the third most frequent cancer type, and its incidence continues to rise gradually worldwide, highlighting the need to identify previously unrecognized molecular events that propel development of this malignancy. Recent evidence suggests that dysregulated expression of FOX family of transcription factors may be critical in various genetic disorders as well as cancer; however, the functional and clinical significance of this pathway in colorectal cancer remains unclear. Herein, we performed a systematic and comprehensive discovery step by evaluating the expression of FOX family members, and identified that FOXM1 and FOXQ1 are frequently overexpressed in colorectal cancer. We subsequently confirmed these findings in two large testing cohorts (n = 550) and an independent clinical validation cohort (n = 134), in which high expression of FOXM1 and FOXQ1 emerged as an independent prognostic factor in colorectal cancer patients. We corroborated these findings by performing functional assays in which knockdown of FOXM1 and FOXQ1 resulted in inhibited cell proliferation and suppressed migration and invasion in colorectal cancer cells. Furthermore, using bioinformatic approaches, we identified miR-342 as a novel regulator of both FOXM1 and FOXQ1. Overexpression or inhibition of miR-342 modulated the expression of both genes and contributed to phenotypic alterations in colorectal cancer cells, which was subsequently validated in a xenograft animal model. Collectively, we have firstly identified FOXM1 and FOXQ1 as promising prognostic biomarkers in colorectal cancer patients, and provided novel evidence that therapeutic targeting of these genes or miR-342 may be a potential treatment approach in colorectal cancer patients. Clin Cancer Res; 22(19); 4947-57. ©2016 AACR.

Clinicopathological and prognostic significance of metastasis-associated in colon cancer-1 (MACC1) overexpression in colorectal cancer: a meta-analysis.

Metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and the increasing amount of evidences suggest that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in colorectal cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of MACC1 overexpression on clinicopathological features and survival outcomes in colorectal cancer. PubMed, CNKI, and Wanfang databases were searched for relevant articles published update to December 2015. Correlation of MACC1 expression level with overall survival (OS), disease-free survival (DFS), and clinicopathological features were analyzed. In this meta-analysis, fifteen studies with a total of 2,161 colorectal cancer patients were included. Our results showed that MACC1 overexpression was significantly associated with poorer OS and DFS. Moreover, MACC1 overexpression was significantly associated with gender, localization, TNM stage, T stage, and N stage. Together, our meta-analysis showed that MACC1 overexpression was significantly associated with poor survival rates, regional invasion and lymph-node metastasis. MACC1 expression level can serve as a novel prognostic factor in colorectal cancer patients.

Abstract 1370: A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application

Abstract Background: Determining RAS mutation status is considered as prognostic factor for colorectal cancer patients in anti-epidermal growth factor receptor (EGFR) antibody therapy. Because genetic testing remains costly and time-consuming, it is necessary to develop mutation specific antibody for immunological analysis. However RAS G12D mutation antibody for immunohistochemical (IHC) staining is not available. Results: Here we report a novel RAS G12D rabbit polyclonal antibody (GTX132407) for immunochemistry (IHC) testing, which was developed by cooperating with GeneTex In. Based on analyzing 15 clinical colorectal cancer specimens, the result of IHC staining using RAS G12D mutation specific antibody (GTX132407) was correlated with genetic testing of RAS G12D mutation using ultra-sensitive total RAS mutation screen kit [Hong Jing Biotechnology Inc. (FemtoPath)]. Conclusion: In summary, the result showed that IHC testing with RAS G12D specific mutation antibody could be a reliable tool for predicting RAS genetic mutation status. Citation Format: Chi-Kuan Chen. A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1370.

Abstract 968: Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer

Abstract Background &amp; Aims: MicroRNAs (miRNAs) play a crucial role in diverse cellular biological processes such as differentiation, proliferation, migration, invasion and survival. MiRNA expression patterns are found to be frequently dysregulated in human tumors, which is currently being exploited both from a basic science perspective and for its clinical usefulness as disease biomarkers. Circulating miRNAs are attracting major interest as potential noninvasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. Methods: Comprehensive miRNA array analysis was performed using serum samples from patients with colorectal neoplasia (CRC: n = 3, adenoma: n = 3) and healthy controls (n = 3). Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. Results: Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly upregulated in patients with colorectal adenomas (P &amp;lt; 0.0001) and cancers (P &amp;lt; 0.0001). Serum miR-1290 levels could robustly distinguish adenoma (area under the curve [AUC] = 0.718) and CRC patients (AUC = 0.830) from normal subjects. Serum miR-1290 levels significantly diminished after surgical resection of the primary tumor in the same patients’ serum specimens (P &amp;lt; 0.0001). In addition, we observed a statistically significant positive correlation of miR-1290 expression levels between primary CRC tissues and matched serum samples (ρ = 0.482; P &amp;lt; 0.0001). High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor in CRC patients (hazard ratio = 4.51; 95% confidence interval = 1.23-23.69; P = 0.0096). Conclusions: Serum miR-1290, which might be secreted from primary CRC, is a novel diagnostic and prognostic biomarker in CRC. Citation Format: Yuji Toiyama, Hiroki Imaoka, Hiroyuki Fujikawa, Junichiro Hiro, Susumu Saigusa, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Takao Mori, Toshio Kato, Ajay Goel, Masato Kusunoki. Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 968.

Abstract 709: In vitro functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients

Abstract Background: PRSS33, one of serine protease multigene family, has central roles in the regulation of a wide variety of physiological processes, including inflammation, development and malignancy. However, the function of this gene in colorectal cancer has not been elucidated. The goal of this study was to evaluate the oncogenic functions of PRSS33 in the colorectal cancer cell line and to evaluate the clinical significance of PRSS33 expression in colorectal cancer patients. Method: PRSS33 was highly expressed in colorectal cancer cell lines, HCT116, SW480 and SW620. The oncogenic functions were evaluated in the cell lines by knocking down PRSS33 with siRNA transfection and compared them with PRSS33 highly expressing control cell lines. The functional studies included cell proliferation assay, invasion assay, migration assay and anchorage-independent semisolid agar colony forming assay. The clinical significance of PRSS33 expression was evaluated in 92 cases of colorectal cancer tissue by immunohistochemistry. Results: The PRSS33 knockdowned cell lines by siRNA transfection showed significant decreases of proliferation, invasion, migration compared to those of control (p&amp;lt;0.05) respectively. The oncogenic function of PRSS33 was confirmed by anchorage-independent semi-solid agar colony forming assay. The PRSS33 knockdowned cell lines revealed lower colony formation on semisolid agar compared to the PRSS33 highly expressing control cell lines. The disease-free survival rate was decreased in patients of PRSS33 high expression (p = 0.001). The overexpression of PRSS33 was associated with survival and death by chi-square test (p = 0.002). Multivariate Cox-regression analysis showed an association between PRSS33 expression and prognosis (HR = 2.71, 95% CI = 1.39-5.27: p = 0.003). Conclusion: This study indicates that PRSS33 is a novel pro-oncogene and the expression is an independent prognostic factor in colorectal cancer patients. In the future, research on the oncogenic signal pathway of PRSS33 in colorectal cancer is necessary. Citation Format: Dongjun Jeong, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Tae Sung Ahn, Tae Hyun Kim, Hyog Young Kwon, Seob Jeon, Sang Byung Bae, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. In vitro functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 709.