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SOX2 Expression Is Regulated by BRAF and Contributes to Poor Patient Prognosis in Colorectal Cancer  [PDF]
Ida V. Lundberg, Anna L?fgren Burstr?m, Sofia Edin, Vincy Ekl?f, ?ke ?berg, Roger Stenling, Richard Palmqvist, Maria L. Wikberg
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101957
Abstract: Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAFV600E mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAFV600E mutated cases. In vitro studies showed that cells expressing the constitutively active BRAFV600E had increased SOX2 expression, a finding not found in cells expressing KRASG12V. Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis.
Venous Thromboembolism Following Colorectal Surgery for Suspected or Confirmed Malignancy  [PDF]
Brenton Sanderson,Kerry Hitos,John P. Fletcher
Thrombosis , 2011, DOI: 10.1155/2011/828030
Abstract: Surgery for colorectal cancer conveys a high risk of venous thromboembolism (VTE). The effect of thromboprophylactic regimens of varying duration on the incidence of VTE was assessed in 417 patients undergoing surgery between 2005 and 2009 for colorectal cancer. Low-dose unfractionated heparin (LDUH) was used in 52.7% of patients, low-molecular-weight heparin (LMWH) in 35.3%, and 10.7% received LDUH followed by LMWH. Pharmacological prophylaxis was continued after hospitalisation in 31.6%. Major bleeding occurred in 4% of patients. The 30-day mortality rate was 1.9%. The incidence of symptomatic VTE from hospital admission for surgery to 12 months after was 2.4%. There were no in-hospital VTE events. The majority of events occurred in the three-month period after discharge, but there were VTE events up to 12 months, especially in patients with more advanced cancer and multiple comorbidities. 1. Introduction Major surgery conveys a significant risk of venous thromboembolism (VTE), a condition that encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE). The first-time incidence of VTE in the general population is approximately 100 persons per 100,000 per year [1]. VTE is a common cause of morbidity and mortality in surgical patients which is preventable in the majority of cases with appropriate prophylaxis [1, 2]. There are numerous risk factors for developing VTE and, importantly, for colorectal cancer surgery patients, include increasing age, history of VTE, malignancy and its treatment, and surgery duration [3–5]. The presence of these risk factors places colorectal cancer surgery patients at an increased risk of VTE compared to general surgical patients [5, 6]. A retrospective analysis examined VTE in colorectal cancer patients, 70% of whom underwent surgery, and found a VTE incidence of 3.1% (2,100 patients) at two years [6]. The incidence rate was found to decrease over the two-year period, demonstrating the importance of VTE prophylaxis in the period after diagnosis and perioperatively [6]. The strongest predictors for VTE occurrence in this patient group were found to be the presence of metastatic disease and multiple co-morbidities [6]. In the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines, colorectal cancer surgery patients are judged as having a high risk of VTE and are recommended to receive both anticoagulant and mechanical VTE prophylaxis unless contraindicated [7]. For anticoagulant prophylaxis, colorectal cancer surgery patients are recommended to receive low-molecular-weight
Iterative local Gaussian clustering for expressed genes identification linked to malignancy of human colorectal carcinoma
Ito Wasito,Siti Zaiton M Hashim,Sri Sukmaningrum
Bioinformation , 2007,
Abstract: Gene expression profiling plays an important role in the identification of biological and clinical properties of human solid tumors such as colorectal carcinoma. Profiling is required to reveal underlying molecular features for diagnostic and therapeutic purposes. A non-parametric density-estimation-based approach called iterative local Gaussian clustering (ILGC), was used to identify clusters of expressed genes. We used experimental data from a previous study by Muro and others consisting of 1,536 genes in 100 colorectal cancer and 11 normal tissues. In this dataset, the ILGC finds three clusters, two large and one small gene clusters, similar to their results which used Gaussian mixture clustering. The correlation of each cluster of genes and clinical properties of malignancy of human colorectal cancer was analysed for the existence of tumor or normal, the existence of distant metastasis and the existence of lymph node metastasis.
Size does not determine the grade of malignancy of early invasive colorectal cancer  [cached]
Takahisa Matsuda, Yutaka Saito, Takahiro Fujii, Toshio Uraoka, Takeshi Nakajima, Nozomu Kobayashi, Fabian Emura, Akiko Ono, Tadakazu Shimoda, Hiroaki Ikematsu, Kuang-I Fu, Yasushi Sano, Takahiro Fujimori
World Journal of Gastroenterology , 2009,
Abstract: AIM: To clarify the clinicopathological characteristics of small and large early invasive colorectal cancers (EI-CRCs), and to determine whether malignancy grade depends on size.METHODS: A total of 583 consecutive EI-CRCs treated by endoscopic mucosal resection or surgery at the National Cancer Center Hospital between 1980 and 2004 were enrolled in this study. Lesions were classified into two groups based on size: small (≤ 10 mm) and large (> 10 mm). Clinicopathological features, incidence of lymph node metastasis (LNM) and risk factors for LNM, such as depth of invasion, lymphovascular invasion (LVI) and poorly differentiated adenocarcinoma (PDA) were analyzed in all resected specimens.RESULTS: There were 120 (21%) small and 463 (79%) large lesions. Histopathological analysis of the small lesion group revealed submucosal deep cancer (sm: ≥ 1000 μm) in 90 (75%) cases, LVI in 26 (22%) cases, and PDA in 12 (10%) cases. Similarly, the large lesion group exhibited submucosal deep cancer in 380 (82%) cases, LVI in 125 (27%) cases, and PDA in 79 (17%) cases. The rate of LNM was 11.2% and 12.1% in the small and large lesion groups, respectively.CONCLUSION: Small EI-CRC demonstrated the same aggressiveness and malignant potential as large cancer.
The Potential Role of ORM2 in the Development of Colorectal Cancer  [PDF]
Xuhua Zhang, Zhiying Xiao, Xiaoyong Liu, Lutao Du, Lili Wang, Shun Wang, Ni Zheng, Guixi Zheng, Wei Li, Xin Zhang, Zhaogang Dong, Xuewei Zhuang, Chuanxin Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031868
Abstract: Colorectal cancer (CRC) is the third most common malignancy in the world. The risk of death is closely correlated to the stage of CRC at the time of primary diagnosis. Therefore, there is a compelling need for the identification of blood biomarkers that can enable early detection of CRC. We used a quantitative proteomic approach with isobaric labeling (iTRAQ) to examine changes in the plasma proteome of 10 patients with CRC compared to healthy volunteers. Enzyme-Linked Immunosorbnent Assay (ELISA) and Western blot were used for further validation. In our quantitative proteomics analysis, we detected 75 human plasma proteins with more than 95% confidence using iTRAQ labeling in conjunction with microQ-TOF MS. 9 up-regulated and 4 down-regulated proteins were observed in the CRC group. The ORM2 level in plasma was confirmed to be significantly elevated in patients suffering from CRC compared with the controls. ORM2 expression in CRC tissues was significantly increased compared with that in corresponding adjacent normal mucous tissues (P<0.001). ITRAQ together with Q-TOF/MS is a sensitive and reproducible technique of quantitative proteomics. Alteration in expression of ORM2 suggests that ORM2 could be used as a potential biomarker in the diagnosis of CRC.
Down-Regulation of Serum/Glucocorticoid Regulated Kinase 1 in Colorectal Tumours Is Largely Independent of Promoter Hypermethylation  [PDF]
Francesca Lessi,Andrew Beggs,Mariagrazia de Palo,Marcello Anti,Raffaele Macarone Palmieri,Simona Francesconi,Vito Gomes,Generoso Bevilacqua,Ian Tomlinson,Stefania Segditsas
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013840
Abstract: We have previously shown that serum/glucocorticoid regulated kinase 1 (SGK1) is down-regulated in colorectal cancers (CRC) with respect to normal tissue. As hyper-methylation of promoter regions is a well-known mechanism of gene silencing in cancer, we tested whether the SGK1 promoter region was methylated in colonic tumour samples.
Identification of expressed genes linked to malignancy of human colorectal carcinoma by parametric clustering of quantitative expression data
Shizuko Muro, Ichiro Takemasa, Shigeyuki Oba, Ryo Matoba, Noriko Ueno, Chiyuri Maruyama, Riu Yamashita, Mitsugu Sekimoto, Hirofumi Yamamoto, Shoji Nakamori, Morito Monden, Shin Ishii, Kikuya Kato
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-3-r21
Abstract: We analyzed the expression levels of 1,536 genes in 100 colorectal cancer and 11 normal tissues using adaptor-tagged competitive PCR, a high-throughput reverse transcription-PCR technique. A parametric clustering method using the Gaussian mixture model and the Bayes inference revealed three groups of expressed genes. Two contained large numbers of genes. One of these groups correlated well with both the differences between tumor and normal tissues and the presence or absence of distant metastasis, whereas the other correlated only with the tumor/normal difference. The third group comprised a small number of genes. Approximately half showed an identical expression pattern, and cancer tissues were classified into two groups by their expression levels. The high-expression group had strong correlation with distant metastasis, and a poorer survival rate than the low-expression group, indicating possible clinical applications of these genes. In addition to c-yes, a homolog of a viral oncogene, prognostic indicators included genes specific to glial cells, which gives a new link between malignancy and ectopic gene expression.The malignancy of human colorectal carcinoma is correlated with a unique expression pattern of a specific group of genes, allowing the classification of tumor tissues into two clinically distinct groups.Gene-expression profiling is a powerful tool with which to elucidate the molecular features underlying variations in individual cancer tissues. Diagnostic and therapeutic applications are the most obvious goals, and have been the main focus of analytical efforts. For example, gene-expression analysis was used successfully to discover a new classification of diffuse B-cell lymphoma, dividing this disease into groups with different prognoses [1].In spite of its increasing popularity, many technical and analytical aspects of gene-expression profiling are still unresolved. Solid tumors such as gastrointestinal or breast cancers are actually mixtures of cance
Elena Dajbog,L.P. Lefter,V. Scripcariu,C. Dragomir
Jurnalul de Chirurgie , 2006,
Abstract: The aetiology of colorectal cancer is heterogeneous, with environment or genetics playing varying key roles. About 80% of patients with colorectal cancer seem to have sporadic disease with no evidence of having inherited the disorder. In the remaining 20%, there seems to be a potentially definable genetic component. Evidence for a genetic contribution to colorectal cancer includes increased risk of colorectal malignancy in persons with a family history and familial aggregation of colorectal cancer consistent with autosomal dominant inheritance. In the past decade, germline genetic mutations conferring high lifetime risk of colorectal cancer in carriers have been found, accounting for 5%–6% of all colorectal cancer cases. Other gene mutations, some with lower lifetime risks, are continuing to be characterized. The translation into clinical practice of genetic discoveries related to hereditary colorectal cancer continues apace, primarily through improved risk assessment by genetic testing. This review analyzes succinctly the most encountered colorectal cancer genetic syndromes of familial adenomatous polyposis and the current availability of genetic tests, describing indications for use of genetic tests in the hereditary colorectal cancer.
Clinical meaning of age-related expression of fecal cytokeratin 19 in colorectal malignancy
Chun-Chao Chang, Shung-Haur Yang, Chih-Cheng Chien, Shu-Hung Chen, Shiann Pan, Chia-Long Lee, Chih-Ming Lin, Hsiao-Lun Sun, Chi-Cheng Huang, Yih-Yiing Wu, Ruey-Neng Yang, Chi-Jung Huang
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-376
Abstract: The quantitation of fecal CK19 transcript was determined by a quantitative real-time reverse transcription polymerase chain in 129 CRC patients (45 younger than 60 years at diagnosis) and 85 healthy controls. The levels of CK19 protein were examined both in colonic cell lines and tissues.The analysis of 45 younger CRC patients (age ≤ 60 years) revealed that patients at the M1 stage had significantly higher expression levels of fecal CK19 mRNA when compared with healthy controls (p < 0.001) and patients at the M0 stage (p = 0.004). Additionally, the degree of consistency between the mean level of fecal CK19 mRNA and the distant metastatic rate in each age interval was up to 89% (p = 0.042).These results indicate that high levels of fecal CK19 mRNA represent a potential marker for colorectal malignancy and for aggressive treatment of younger CRC patients.Colorectal cancer (CRC), which is a predominant gastrointestinal malignancy, is one of the most commonly diagnosed tumors in both men and women, and is becoming one of the major medical causes of economic burden worldwide [1]. On average, the starting age of CRC incidence begins at 40 years of age and rises sharply at the age of 50-55 years [2]. Moreover, CRC is also the second most common cause of cancer-related deaths among men over 40 years of age [3].Several clinicopathological features of CRC have been studied to identify markers that could predict CRC outcomes [4]. Numerous studies have shown that metastasis through the blood or lymphatic vessels is a major complication of cancer, and affects the prognosis of patients with primary carcinomas [5], therefore, methods developed to detect disseminated tumor cells in the peripheral blood and lymph nodes of patients have been evaluated. Many genetic changes were found in metastatic tumors, and some of them could be molecular markers for disseminated tumor cells [6]. CRC development and progression were shown to be complex processes that are associated with multiple ge
Newer techniques in diagnostic imaging of colorectal carcinoma
Lu?i? M.A.,Miu?in-Vukadinovi? I.S.,Lu?i? S.M.,Koprivek K.M.
Acta Chirurgica Iugoslavica , 2009, DOI: 10.2298/aci0904113l
Abstract: A wide spectrum of nowadays availible radiological and imaging methods in the diagnostic evaluation of patients with colorectal cancer enabled not only the improvement of primary colorectal malignancy detection, precise staging, regional involvement and metastatic spread assessment, but also the posttherapeutical estimation and follow- up. Having in mind that the exact diagnostic assessment of colorectal carcinoma by use of different imaging modalities still raises a lots of contradictories, in this report we have tried to present the possibilities of newer imaging techniques in the diagnostic evaluation of the patients with colorectal cancer.
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