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Top down or bottom up? Competing management structures in the morphogenesis of colorectal neoplasms
  1. N A Wright,
  2. R Poulsom
  1. Histopathology Unit, Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK, and Department of Histopathology, Bart’s and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, UK
  1. Correspondence to:
    Professor N A Wright, Histopathology Unit, Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK;
    warden{at}qmul.ac.uk

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Modifier genes may influence the severity, or adenoma number, of familial adenomatous polyposis in humans through tumour initiation rather than progression

One of the earliest tumour suppressor genes to be identified was APC. Germline mutations in APC are found in familial adenomatous polyposis (FAP) and second hits lead to the development of often many hundreds of adenomas in the colon and rectum, some of which progress to cancer if untreated. Many sporadic adenomas, and their ensuing carcinomas, show APC mutations, and FAP remains an important paradigm for the commoner sporadic form. Thus recent studies from the Tomlinson laboratory1 show a very close linear relationship between the macroscopic—or naked eye—count of adenomas in excised FAP colons and the count made microscopically from adenomas occupying one crypt (the unicryptal or monocryptal adenoma, fig 1) upwards. Such a close relationship strongly indicates that progression from microadenomas to macroscopic size is essentially random, that variation in disease severity (number of adenomas) results from differences in the number of microadenomas rather than disease progression, and importantly, that the selective advantages provided by different APC mutations act on tumour initiation rather than progression. A paper in this issue of Gut, also from the Tomlinson laboratory,2 analyses the effects of putative modifier genes: the severity of the disease was related to the site of the mutation, as might be expected, but first degree relatives showed polyp counts which were more similar than more distant relatives [see page 420]. These observations indicate that modifier genes influence the severity of FAP, again through tumour initiation. Furthermore, the finding of a constant microadenoma density as the colon is traversed1 suggests that initiation …

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