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Familial Cancer

, Volume 9, Issue 3, pp 389–393 | Cite as

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

  • O. C. WillEmail author
  • S. J. Leedham
  • G. Elia
  • R. K. S. Phillips
  • S. K. Clark
  • I. P. M. Tomlinson
Article

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.

Keywords

APC Colorectal cancer ‘just right’ Wnt signalling Two-hit hypothesis Polyposis 

Abbreviations

FAP

Familial adenomatous polyposis

APC

Adenomatous polyposis coli

LOH

Loss of heterozygosity

Notes

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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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • O. C. Will
    • 1
    • 2
    Email author
  • S. J. Leedham
    • 3
  • G. Elia
    • 3
  • R. K. S. Phillips
    • 1
  • S. K. Clark
    • 1
  • I. P. M. Tomlinson
    • 2
    • 4
  1. 1.Polyposis RegistrySt Mark’s HospitalHarrowUK
  2. 2.Molecular and Population Genetics LaboratoryLondon Research Institute, Cancer Research UKLondonUK
  3. 3.Histopathology UnitLondon Research Institute, Cancer Research UKLondonUK
  4. 4.Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK

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