A combined ULBP2 and SEMA5A expression signature as a prognostic and predictive biomarker for colon cancer

Background: Prognostic biomarkers for cancer have the power to change the course of disease if they add value beyond known prognostic factors, if they can help shape treatment protocols, and if they are reliable. The aim of this study was to identify such biomarkers for colon cancer and to understand the molecular mechanisms leading to prognostic stratifications based on these biomarkers. Methods and Findings: We used an in house R based script (SSAT) for the in silico discovery of stage-independent prognostic biomarkers using two cohorts, GSE17536 and GSE17537, that include 177 and 55 colon cancer patients, respectively. This identified 2 genes, ULBP2 and SEMA5A, which when used jointly, could distinguish patients with distinct prognosis. We validated our findings using a third cohort of 48 patients ex vivo. We find that in all cohorts, a combined ULBP2/SEMA5A classification (SU-GIB) can stratify distinct prognostic sub-groups with hazard ratios that range from 2.4 to 4.5 (p=0.01) when overall- or cancer-specific survival is used as an end-measure, independent of confounding prognostic parameters. In addition, our preliminary analyses suggest SU-GIB is comparable to Oncotype DX colon(®) in predicting recurrence in two different cohorts (HR: 1.5-2; p=0.02). SU-GIB has potential as a companion diagnostic for several drugs including the PI3K/mTOR inhibitor BEZ235, which are suitable for the treatment of patients within the bad prognosis group. We show that tumors from patients with worse prognosis have low EGFR autophosphorylation rates, but high caspase 7 activity, and show upregulation of pro-inflammatory cytokines that relate to a relatively mesenchymal phenotype. Conclusions: We describe two novel genes that can be used to prognosticate colon cancer and suggest approaches by which such tumors can be treated. We also describe molecular characteristics of tumors stratified by the SU-GIB signature. © Ivyspring International Publisher

Colon cancer associated transcript-1: A novel RNA expressed in malignant and pre-malignant human tissues

Early detection of colorectal cancer (CRC) is currently based on fecal occult blood testing (FOBT) and colonoscopy, both which can significantly reduce CRC-related mortality. However, FOBT has low-sensitivity and specificity, whereas colonoscopy is labor- and cost-intensive. Therefore, the discovery of novel biomarkers that can be used for improved CRC screening, diagnosis, staging and as targets for novel therapies is of utmost importance. To identify novel CRC biomarkers we utilized representational difference analysis (RDA) and characterized a colon cancer associated transcript (CCAT1), demonstrating consistently strong expression in adenocarcinoma of the colon, while being largely undetectable in normal human tissues (p < 000.1). CCAT1 levels in CRC are on average 235-fold higher than those found in normal mucosa. Importantly, CCAT1 is strongly expressed in tissues representing the early phase of tumorigenesis: in adenomatous polyps and in tumor-proximal colonic epithelium, as well as in later stages of the disease (liver metastasis, for example). In CRC-associated lymph nodes, CCAT1 overexpression is detectable in all H&E positive, and 40.0% of H&E and immunohistochemistry negative lymph nodes, suggesting very high sensitivity. CCAT1 is also overexpressed in 40.0% of peripheral blood samples of patients with CRC but not in healthy controls. CCAT1 is therefore a highly specific and readily detectable marker for CRC and tumor-associated tissues. Copyright © 2011 UICC

Diagnostic value of preoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 in colorectal cancer

BACKGROUND: Since the first introduction of tumour markers, their usefulness for diagnosis has been a challenging question. The aim of the present prospective study was to investigate, in colorectal cancer patients, the relationship between preoperative tumour marker concentrations and various clinical variables. METHODS: The study prospectively enrolled 131 consecutive patients with a confirmed diagnosis of colorectal carcinoma and 131 age- and sex-matched control subjects with no malignancy. The relationships of the tumour markers carcinoembryonic antigen (cea) and carbohydrate antigen (ca) 19-9 with disease stage, tumour differentiation (grade), mucus production, liver function tests, T stage, N stage, M stage were investigated. RESULTS: Serum concentrations of cea were significantly higher in the patient group than in the control group (p = 0.001); they were also significantly higher in stage iii (p = 0.018) and iv disease (p = 0.001) than in stage i. Serum concentrations of cea were significantly elevated in the presence of spread to lymph nodes (p = 0.005) in the patient group. Levels of both tumour markers were significantly elevated in the presence of distant metastasis in the patient group (p = 0.005 for cea; p = 0.004 for ca 19-9). CONCLUSIONS: Preoperative levels of cea and ca 19-9 might provide an estimate of lymph node invasion and distant metastasis in colorectal cancer patients

Effect of intraoperative PEEP application on colonic anastomoses healing: An experimental animal study

This study aimed to assess the effect of intraoperative positive end–expiratory pressure (PEEP) intervention on the healing of colonic anastomoses in rabbits. A total of 32 New Zealand type male rabbits were divided into 2 groups of 16 animals each. Following ventilation with tracheostomy, colonic resection and anastomosis were performed in both groups. Although 10 cm of H2O PEEP level was applied in group 1 (PEEP), group 2 [zero end-expiratory pressure (ZEEP)] was ventilated without PEEP throughout the surgery. Half of both the PEEP and ZEEP group animals were killed on the third postoperative day, whereas the remaining half were killed on the seventh. Anastomotic bursting pressures, the tissue concentrations in hydroxyproline, and histologic assessments were performed. Intraoperative oxygen saturation and postoperative arterial blood gas parameters were also compared. On the first postoperative day, both arterial oxygen tension (PO2) and oxygen saturation (SO2) in the PEEP group were significantly higher than in the ZEEP group. On the seventh postoperative day, the bursting pressures of the anastomoses were significantly higher in the PEEP group; however, the hydroxyproline content was significantly lower in the PEEP group than in the ZEEP group. At day 7, the PEEP group was significantly associated with increased neoangiogenesis compared with the ZEEP group. The anastomotic healing process is positively influenced by the intraoperative PEEP application.</jats:p