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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    • "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 · 2.71 Impact Factor
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    • "Colorectal cancer is amongst the top ranking cancers that have a high mortality rate worldwide [1]. It occurs as a result of genetic and epigenetic changes of normal glandular epithelial cells into invasive adenocarcinoma [2]. The treatment for colorectal cancer remains a challenge due to the high metastatic incidence and recurrence of the disease [3], as well as toxicity caused by chemotherapeutic drugs to noncancerous cells. "
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    ABSTRACT: Colorectal cancer is the third most commonly diagnosed cancer. Amongst treatments that have been explored, photodynamic therapy (PDT) is a treatment that is of interest as it poses ideal advantages such as affinity for cancer cells. This study aimed to determine the correlation between the localization site of a sulfonated zinc phthalocyanine (ZnPcS mix) photosensitizer (PS) and its associated cell death pathway in vitro in colorectal cancer cell lines (DLD-1 and CaCo-2). Visible morphological changes were observed in PDT treated cells after 24 h. Reactive oxygen species (ROS) were detected and visualized 1 h after PDT. ZnPcS mix was predominantly localized in lysosomes and partially in the mitochondria. FITC Annexin V staining showed a significant decrease in the percentage of viable DLD-1 and CaCo-2 cells 24 h after PDT, with an increase in apoptotic cell population. Moreover, there was a significant increase in both cathepsin D and cytochrome C at 1 and 24 h. In conclusion, ZnPcS mix showed the ability of inducing apoptotic cell death features in PDT treated cells.
    International Journal of Photoenergy 03/2014; 2014. DOI:10.1155/2014/383027 · 2.66 Impact Factor
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    • "We are therefore confident that our proportion of MACS-CRCs is not due to false-negative flow cytometry results. Our data strongly challenge the dogma that CRCs can all be dichotomised into tumours which progress along either the MSI or CIN pathway (Fearon 2011; Pritchard & Grady 2011). We have shown that a significant proportion of CRCs belong to a third group which involves neither CIN nor MSI. "
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    ABSTRACT: Colorectal cancers (CRC) are thought to have genetic instability in the form of either microsatellite instability (MSI) or chromosomal instability (CIN). Recently, tumours have been described without either MSI or CIN, that is, microsatellite and chromosome stable (MACS) CRCs. We investigated the (i) frequency of the MACS-CRCs and (ii) whether this genotype predicted responsiveness to neoadjuvant chemoradiotherapy. To examine the frequency of MACS-CRCs, DNA content (ploidy) was examined in 89 sporadic microsatellite-stable CRCs using flow cytometry. The tumours were also screened for mutations in KRAS/BRAF/TP53/PIK3CA by QMC-PCR. To examine the value of tumour ploidy in predicting response to chemoradiotherapy, DNA content was tested in a separate group of 62 rectal cancers treated with neoadjuvant chemoradiotherapy. Fifty-one of 89 CRCs (57%) were aneuploid and 38 (43%) were diploid. There was no significant association between mutations in TP53/KRAS/BRAF/PIK3CA and ploidy. Testing of association between mutations revealed only mutual exclusivity of KRAS/BRAF mutation (P < 0.001). Of the 62 rectal cancers treated with neoadjuvant chemoradiotherapy, 22 had responded (Mandard tumour regression grade 1/2) and 40 failed to respond (Grade 3-5). Twenty-five of 62 (40%) tumours were diploid, but there was no association between ploidy and response to therapy. We conclude that MACS-CRCs form a significant proportion of microsatellite-stable CRCs with a mutation profile overlapping that of CRCs with CIN. A diploid genotype does not, however, predict the responsiveness to radiotherapy.
    International Journal of Experimental Pathology 02/2014; 95(1):16-23. DOI:10.1111/iep.12070 · 2.05 Impact Factor


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