CpG island methylation phenotype (CIMP) in oral cancer: Associated with a marked inflammatory response and less aggressive tumour biology

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Oral Oncology
Volume 43, Issue 9, October 2007, Pages 878-886

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CpG island methylation phenotype (CIMP) in oral cancer: Associated with a marked inflammatory response and less aggressive tumour biology
Richard J. Shawa, c, Gillian L. Hall, d, Derek Lowe, e, Naomi L. Bowers, b, Triantafillos Liloglou, b, John K. Field, a, b, Julia A. Woolgar, d and Janet M. Risk, a
a - Molecular Genetics and Oncology Group, School of Dental Sciences, University of Liverpool, Liverpool L69 3GN, UK
b - University of Liverpool Cancer Research Centre, Roy Castle Lung, Cancer Research Programme, 200 London Road, Liverpool L3 9TA, UK
c - Regional Maxillofacial Unit, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK
d - Department of Oral Pathology, School of Dental Sciences, University of Liverpool, Liverpool L69 3GN, UK
e - Medical Statistician, Regional Maxillofacial Unit, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK

Received 5 September 2006; revised 22 October 2006; accepted 23 October 2006. Available online 25 January 2007.

Summary
Studies in several tumour sites highlight the significance of the CpG island methylation phenotype (CIMP), with distinct features of histology, biological aggression and outcome. We utilise pyrosequencing techniques of quantitative methylation analysis to investigate the presence of CIMP in oral squamous cell carcinoma (OSCC) for the first time, and evaluate its correlation with allelic imbalance, pathology and clinical behaviour. Tumour tissue, control tissue and PBLs were obtained from 74 patients with oral squamous cell carcinoma. Pyrosequencing was used to analyse methylation patterns in 75Ò200 bp regions of the CpG rich gene promoters of 10 genes with a broad range of cellular functions. Allelic imbalance was investigated using a multiplexed panel of 11 microsatellite markers. Corresponding variables, histopathological staging and grading were correlated with these genetic and epigenetic aberrations. A cluster of tumours with a greater degree of promoter methylation than would be predicted by chance alone (P = 0.001) were designated CIMP+ve. This group had less aggressive tumour biology in terms of tumour thickness (p = 0.015) and nodal metastasis (P = 0.012), this being apparently independent of tumour diameter. Further, it seems that these CIMP+ve tumours excited a greater host inflammatory response (P = 0.019). The exact mechanisms underlying CIMP remain obscure but the association with a greater inflammatory host response supports existing theories relating these features in other tumour sites. As CIMP has significant associations with other well documented prognostic indicators, it may prove beneficial to include methylation analyses in molecular risk modelling of tumours.

Keywords: CIMP; Oral squamous cell carcinoma; Methylation; Allelic imbalance

Corresponding author. Address: Molecular Genetics and Oncology Group, Department of Clinical Dental Sciences, University of Liverpool, Liverpool L69 3GN, UK. Tel.: +44 151 529 5290; fax: +44 151 529 5288.

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