Colorectal cancer molecular biology moves into clinical practice

Department of Laboratory Medicine, University of Washington, Washington, USA.
Gut (Impact Factor: 14.66). 10/2010; 60(1):116-29. DOI: 10.1136/gut.2009.206250
Source: PubMed


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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    • "For therapy purposes, anti-VEGF-A antibodies have been employed in addition to standard chemotherapy agents. Despite all the efforts, the prognosis of patients with advanced stage disease has not been significantly improved [54] [55]. hERG1 protein is highly expressed in colorectal adenocarcinomas with respect to hyperplastic lesions of the colon [11] and in CRC cell lines [11] [33] and it was demonstrated that the protein is not expressed in small adenomas and sigma diverticulitis [56]. "
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    ABSTRACT: Because of their high incidence and mortality solid cancers are a major health problem worldwide. Although several new biomarkers and potential targets for therapy have been identified through biomolecular research in the last years, the effects on patients' outcome are still unsatisfactory. Increasing evidence indicates that hERG1 potassium channels are overexpressed in human primary cancers of different origin and several associations between hERG1 expression and clinicopathological features and/or outcome are emerging. Aberrant hERG1 expression may be exploited either for early diagnosis (especially in those cancers where it is expressed in the initial steps of tumor progression) or for therapy purposes. Indeed, hERG1 blockage impairs tumor cell growth both in vitro and in vivo in preclinical mouse model. hERG1-based tumor therapy in humans, however, encounters the major hindrance of the potential cardiotoxicity that many hERG1 blockers exert. In this review we focus on recent advances in translational research in some of the most frequent human solid cancers (breast, endometrium, ovary, pancreas, esophagus, stomach, and colorectum) that have been shown to express hERG1 and that are a major health problem.
    09/2015; 2015:896432. DOI:10.1155/2015/896432
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    • "Despite a growing awareness of the molecular heterogeneity of CRC, comparatively few studies have evaluated CRC risk in relation to its various molecular phenotypes [32]–[35]. To our knowledge, the relationship between obesity, KRAS mutation status and CRC risk has only been investigated in a few previous studies. "
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    ABSTRACT: Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmö Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRAS-mutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.
    PLoS ONE 06/2014; 9(6):e98964. DOI:10.1371/journal.pone.0098964 · 3.23 Impact Factor
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    • "Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with a rapidly increasing incidence in China in the past decade [1]. CRC originates from the accumulation of acquired genetic and epigenetic alterations that lead to the transformation of normal epithelial cells to invasive adenocarcinomas at the cellular level [2] [3]. There are two distinct pathways identified in CRC: (i) microsatellite instability (MSI) pathway with gain or loss of repeat units in a germline microsatellite allele as well as defects in the mismatch repair mechanisms and (ii) chromosomal instability (CIN) pathway with gain or loss of chromosomal regions [4]. "
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    ABSTRACT: Background: MicroRNA (miRNA) is a short and endogenous RNA molecule that regulates posttranscriptional gene expression. It is an important factor for tumorigenesis of colorectal cancer (CRC), and a potential biomarker for diagnosis, prognosis, and therapy of CRC. Our objective is to identify the related miRNAs and their associations with genes frequently involved in CRC microsatellite instability (MSI) and chromosomal instability (CIN) signaling pathways. Results: A regression model was adopted to identify the significantly associated miRNAs targeting a set of candidate genes frequently involved in colorectal cancer MSI and CIN pathways. Multiple linear regression analysis was used to construct the model and find the significant mRNA-miRNA associations. We identified three significantly associated mRNA-miRNA pairs: BCL2 was positively associated with miR-16 and SMAD4 was positively associated with miR-567 in the CRC tissue, while MSH6 was positively associated with miR-142-5p in the normal tissue. As for the whole model, BCL2 and SMAD4 models were not significant, and MSH6 model was significant. The significant associations were different in the normal and the CRC tissues. Conclusion: Our results have laid down a solid foundation in exploration of novel CRC mechanisms, and identification of miRNA roles as oncomirs or tumor suppressor mirs in CRC.
    BioMed Research International 05/2014; 2014:676724. DOI:10.1155/2014/676724 · 3.17 Impact Factor
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