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Location in the large bowel influences the APC mutations observed in FAP adenomas

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Abstract

The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1–2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations.

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Abbreviations

FAP:

Familial adenomatous polyposis

APC:

Adenomatous polyposis coli

LOH:

Loss of heterozygosity

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Acknowledgments

The authors thank Jules Harvey, and Kay Neale and colleagues from the St Mark’s Hospital Polyposis Registry, for their assistance in sample collection. Olivia Will was funded by St Mark’s Hospital Polyposis Registry and Cancer Research UK.

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Authors and Affiliations

  1. Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, HA1 3UJ, UK

    O. C. Will, R. K. S. Phillips & S. K. Clark

  2. Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, WC2A 3PX, UK

    O. C. Will & I. P. M. Tomlinson

  3. Histopathology Unit, London Research Institute, Cancer Research UK, London, WC2A 3PX, UK

    S. J. Leedham & G. Elia

  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK

    I. P. M. Tomlinson

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  1. O. C. Will
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  2. S. J. Leedham
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  3. G. Elia
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  4. R. K. S. Phillips
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Correspondence to O. C. Will.

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Will, O.C., Leedham, S.J., Elia, G. et al. Location in the large bowel influences the APC mutations observed in FAP adenomas. Familial Cancer 9, 389–393 (2010). https://doi.org/10.1007/s10689-010-9332-y

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  • DOI: https://doi.org/10.1007/s10689-010-9332-y

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