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Field defects in DNA repair: is loss of MGMT an initial event in colorectal carcinogenesis?
  1. Trevor A Graham1,
  2. Simon J Leedham2
  1. 1Histopathology Laboratory, Cancer Research UK London Research Institute, London, UK
  2. 2Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  1. Correspondence to Trevor A Graham, Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK; trevor.graham{at}cancer.org.uk

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The classical view of carcinogenesis begins with rate-limiting mutations in a tumour suppressor or oncogene resulting in immediate lesion growth. Tumour progression occurs as cells within the tumour acquire additional mutations; this is the Somatic Mutation Theory of carcinogenesis.1 However, it is increasingly clear that the road to cancer can begin long before any overt tumour growth; this is termed ‘pretumour progression’.

Pretumour mutations are the likely drivers of ‘field cancerisation’—the widespread replacement of the normal cell population with a histologically non-dysplastic but protumorigenic clone that harbours a genetic or epigenetic alteration.2–4 Identifying situations of field cancerisation has obvious clinical significance: (1) identifying protumorigenic fields may predict a patient's risk of neoplastic progression; and (2) limited tumour resections in situations where field cancerisation has occurred may leave significant residual disease.

Field cancerisation has been reported in many different tissues. In their seminal paper, Slaughter and colleagues recognised that field cancerisation could underlie the development of multifocal head and neck cancers.2 Subsequently, there has been unequivocal evidence of field cancerisation in many other tissues, most notably in the lung,5 in the development of Barrett's oesophagus-associated adenocarcinoma6 and in the inflammatory bowel disease ulcerative colitis.7 In each of these cases the identified mutant …

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