APC mutation and tumour budding in colorectal cancer

Department of Molecular and Cellular Pathology, University of Queensland, Queensland 4006, Australia.
Journal of Clinical Pathology (Impact Factor: 2.92). 02/2003; 56(1):69-73.
Source: PubMed


To determine the frequency of tumour budding and somatic APC mutation in a series of colorectal cancers stratified according to DNA microsatellite instability (MSI) status. Material/Methods: Ninety five colorectal cancers were genotyped for APC mutation in the mutation cluster region (exon 15) and scored for the presence of tumour budding at the invasive margin in haematoxylin and eosin stained sections. A subset was immunostained for beta catenin and p16.
The frequency of both somatic APC mutation and tumour budding increased pari passu in cancers stratified as sporadic MSI high (MSI-H), hereditary non-polyposis colorectal cancer (HNPCC), MSI low (MSI-L), and microsatellite stable (MSS). Both budding and APC mutation were significantly less frequent in sporadic MSI-H cancers than in MSI-L or MSS cancers. Tumour buds were characterised by increased immunostaining for both beta catenin and p16.
Tumour budding is associated with an adverse prognosis. The lack of budding in MSI-H colorectal cancer may account for the improved prognosis of this subset and may be explained by an intact WNT signalling pathway and/or inactivated p16(INK4a).

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Available from: Michael D Walsh, Mar 10, 2014
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    • "Biologically, tumor buds may transiently acquire a mesenchymal phenotype due to loss of E-cadherin expression and nuclear translocation of β-catenin leading to activation of WNT signaling (6, 34). Upregulation of metalloproteinases, urokinase receptor, and cathepsin may contribute to an increased migratory capacity and stromal invasion (35, 36). "
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    ABSTRACT: The basis of personalized medicine in oncology is the prediction of an individual's risk of relapse and death from disease. The presence of tumor budding (TB) at the tumor-host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of dedifferentiated cells or small clusters of up to five cells at the tumor invasive front and can be observed in aggressive carcinomas of the esophagus, stomach, pancreas, ampulla, colon, and rectum. Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis. The UICC has officially recognized TB as additional independent prognostic factor in cancers of the colon and rectum. Recent studies have also characterized TB as a promising prognostic indicator for clinical management of esophageal squamous cell carcinoma, adenocarcinoma of the gastro-esophageal junction, and gastric adenocarcinoma. However, several important issues have to be addressed for application in daily diagnostic practice: (1) validation of prognostic scoring systems for TB in large, multi-center studies, (2) consensus on the optimal assessment method, and (3) inter-observer reproducibility. This review provides a comprehensive analysis of TB in cancers of the upper gastrointestinal tract including critical appraisal of perspectives for further study.
    Full-text · Article · Aug 2014 · Frontiers in Oncology
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    • "Strong points of the present study include the selection of the biomarker and the practical approach. Tumour budding is a robust histomorphological marker and declared an independent prognostic factor by many different studies, independently of the selected scoring system (Hase et al, 1993; Okuyama et al, 2002, 2003; Ueno et al, 2002, 2004; Jass et al, 2003; Nakamura et al, 2005; Park et al, 2005; Horkko et al, 2006; Choi et al, 2007; Lugli et al, 2009; Wang et al, 2009). These results are biologically not surprising as tumour buds likely represent an epithelial-mesenchymal transition (EMT)-like process, express proteins of tumour aggressiveness such as matrix-metalloproteinases, nuclear bcatenin , VEGF, p16 and some potential stem cell markers in association with loss of adhesion molecules such as E-cadherin (Zlobec and Lugli, 2010). "
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    ABSTRACT: Background: In colorectal cancer (CRC), tumour budding at the invasion front is associated with lymph node (LN) and distant metastasis. Interestingly, tumour budding can also be detected in biopsies (intratumoural budding; ITB) and may have similar clinical importance. Here we investigate whether ITB in preoperative CRC biopsies can be translated into daily diagnostic practice. Methods: Preoperative biopsies from 133 CRC patients (no neoadjuvant therapy) underwent immunohistochemistry for pan-cytokeratin marker AE1/AE3. Across all biopsies for each patient, the densest region of buds at × 40 (high-power field; HPF) was identified and buds were counted. Results: A greater number of tumour buds in the biopsy was associated with pT stage (P=0.0143), LN metastasis (P=0.0007), lymphatic (P=0.0065) and venous vessel invasion (P=0.0318) and distant metastasis (cM1) (P=0.0013). Using logistic regression, a ‘scale' was developed to estimate the probability of LN and distant metastasis using the number of tumour buds (e.g. 10 buds per HPF: 64% chance of LN metastasis; 30 buds per HPF: 86% chance). Inter-observer agreement for ITB was excellent (intraclass correlation coefficient: 0.813). Conclusion: Tumour budding can be assessed in the preoperative biopsy of CRC patients. It is practical, reproducible and predictive of LN and distant metastasis. Intratumoural budding qualifies for further investigation in the prospective setting.
    Full-text · Article · Dec 2013 · British Journal of Cancer
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    • "De nombreux auteurs ont proposé de considérer toutes les TVID comme des tumeurs d'emblée invasives [1,2,10,22—24]. Cependant, des études plus récentes ont évoqué la possibilité que le phénotype moléculaire des TVID soit distinct des tumeurs T3 classiques, notamment du fait de l'absence du besoin pour la tumeur d'acquérir l'arsenal moléculaire permettant de progresser dans le muscle vésical [4] [25]. "
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    ABSTRACT: Introduction Cancer Committee of the French Association of Urology (CCAFU) conducted a review of the epidemiology, diagnosis and treatment of intradiverticular bladder tumours (TVID) and proposed therapeutic management. Material and methods A bibliographic research in French and English using Medline® with the keywords “tumor”, “bladder” and “diverticulum” was performed. Results TVID are more frequently of stage T ≥ 3a and with non urothelial histology than classical bladder tumors. At diagnosis, the risk of underestimation of the extent and multifocality of the tumor was described. Their prognosis, that was more pejorative than conventional tumors, should impelled to limit the indications of conservative treatment. The evidence levels of analyzed publications were low, with C level according to Sackett score. Conclusion the specificities of the TVID have lead the CCAFU to propose specific therapeutic guidelines, based on poor evidence level. Ta-T1 low grade TVID can be treated by transurethral resection alone or followed by BCG therapy in cases of associated carcinoma in situ. High-grade TVID, unifocal and without associated carcinoma in situ, can be treated by diverticulectomy associated with pelvic lymphadenectomy. High grade TVID, multiple or associated with carcinoma in situ, warranted total cystectomy.
    Full-text · Article · Jul 2012 · Progrès en Urologie
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