Colorectal cancer molecular biology moves into clinical practice

Department of Laboratory Medicine, University of Washington, Washington, USA.
Gut (Impact Factor: 13.32). 10/2010; 60(1):116-29. DOI: 10.1136/gut.2009.206250
Source: PubMed

ABSTRACT The promise of personalised medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the recent advances in testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers) and the prediction of treatment responses (predictive markers) are examined.

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    ABSTRACT: Background Several clinical and pathological factors have an impact on the prognosis of colorectal cancer (CRC), but they are not yet adequate for risk assessment. We aimed to identify a molecular signature that can reliably identify CRC patients at high risk for recurrence.ResultsTwo hundred eighty-one CRC samples (stage II/III) were included in this study. A two-step gene expression profiling study was conducted. First, gene expression measurements from 81 fresh frozen CRC samples were obtained using Affymetrix Human Genome U133 Plus 2.0 Arrays. Second, a focused gene expression assay, including prognostic genes and genes of interest from literature reviews, was performed using 200 fresh frozen samples and a Taqman low-density array (TLDA) analysis. An optimal 31-gene expression classifier for the prediction of recurrence among patients with stage II/III CRC was developed using logistic regression analysis. This gene expression signature classified 58.5% of patients as low-risk and 41.5% as high-risk (P¿<¿0.001). The signature was the strongest independent prognostic factor in the multivariate analysis. The five-year relapse-free survival (RFS) rates for the low-risk patients and the high-risk patients were 88.5% and 41.3% (P¿<¿0.001), respectively.Conclusion We identified a 31-gene expression signature that is closely associated with the clinical outcome of stage II/III CRC patients.
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    ABSTRACT: Transforming growth factor-beta-induced (TGFBI) serves as a linker protein and plays a role in the activation of morphogenesis, cell proliferation, adhesion, migration, differentiation and inflammation. High expression levels of the human TGFBI gene are correlated with numerous human malignancies. In order to explore the roles of TGFBI in the tumor progression of colorectal cancer, colorectal cancer specimens from 115 patients with strict follow-up were selected for the analysis of TGFBI by immunohistochemistry. The correlations between TGFBI expression and the clinicopathological features of colorectal cancers were evaluated. In the colorectal cancer tissues, TGFBI was mainly localized in the cytoplasm and stroma and scarcely in the nucleus. TGFBI expression in the cytoplasm and stroma was not found to be associated with age, gender, tumor histopathological grading, PT category and tumor location (P > 0.05 for each). However, high TGFBI expression in the cytoplasm and stroma correlated with lymph node metastasis, distant metastasis and Dukes stage (P < 0.05 for each). The survival rate was significantly lower in patients with high TGFBI expression than in those with low TGFBI expression. Furthermore, we found that tumor node metastasis (TNM) staging (HR: 2.963; 95% CI: 1.573-1.664; P = 0.000), differentiation (HR: 1.574; 95% CI: 1.001-2.476; P = 0.049) and high TGFBI cytoplasmic expression (HR: 3.332; 95% CI: 1.410-7.873; P = 0.000) proved to be independent prognostic factors for survival in colorectal cancer. In conclusion, TGFBI plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor for colorectal cancer patients.
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    ABSTRACT: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95%CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.
    BMC Cancer 12/2015; 15(1):1144. DOI:10.1186/s12885-015-1144-x · 3.32 Impact Factor


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