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Exon 3 β-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome
  1. V Johnson1,
  2. E Volikos1,
  3. S E Halford3,
  4. E T Eftekhar Sadat2,
  5. S Popat5,
  6. I Talbot2,
  7. K Truninger6,
  8. J Martin1,
  9. J Jass7,
  10. R Houlston5,
  11. W Atkin1,
  12. I P M Tomlinson4,
  13. A R J Silver1
  1. 1Cancer Research UK Colorectal Cancer Unit, St Mark’s Hospital, Harrow, UK
  2. 2Academic Department of Pathology, St Mark’s Hospital, Harrow, UK
  3. 3Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK
  4. 4Cancer Research UK Colorectal Cancer Unit, St Mark’s Hospital, Harrow, UK, and Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK
  5. 5Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK
  6. 6Division of Gastroenterology, Catonal Hospital Aarau, Switzerland
  7. 7Department of Pathology, Duff Medical Building, Montreal, Canada
  1. Correspondence to:
    Dr A Silver
    Cancer Research UK, Colorectal Cancer Unit, St Mark’s Hospital, Harrow, HA1 3UJ, UK; andrew.silvercancer.org.uk

Abstract

Background and aim: Activating β-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that β-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of β-catenin mutation frequency in each tumour type.

Methods: Direct sequencing of exon 3 of β-catenin.

Results: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic β-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI−) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p = 0.035) and in both MSI− (p<0.0001) and MSI+ (p = 0.008) sporadic cancers. Mutations were more common in higher stage (Dukes’ stages C and D) cancers (p = 0.001).

Conclusion: Exon 3 β-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.

  • MSI+, microsatellite unstable
  • MSI−, microsatellite stable
  • HNPCC, hereditary non-polyposis colorectal cancer
  • GSK3β, glycogen synthase kinase 3-B
  • APC, adenomatous polyposis coli
  • PCR, polymerase chain reaction
  • β-catenin
  • colorectal carcinomas
  • hereditary non-polyposis colorectal cancer syndrome
  • mutation

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Footnotes

  • Conflict of interest: None declared.