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BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing
  1. E Domingo1,
  2. P Laiho2,
  3. M Ollikainen2,
  4. M Pinto3,
  5. L Wang4,
  6. A J French4,
  7. J Westra5,
  8. T Frebourg6,
  9. E Espín1,
  10. M Armengol1,
  11. R Hamelin7,
  12. H Yamamoto8,
  13. R M W Hofstra5,
  14. R Seruca3,
  15. A Lindblom9,
  16. P Peltomäki2,
  17. S N Thibodeau4,
  18. L A Aaltonen2,
  19. S Schwartz, Jr1
  1. 1Centre d’Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain
  2. 2Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
  3. 3Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-465 Porto, Portugal
  4. 4Mayo Clinic College of Medicine, Rochester, MN, USA
  5. 5Clinical Genetics Centre, Groningen University Hospital, A. Deusinglaan 4, 9713 AW Groningen, The Netherlands
  6. 6Service de Génétique, CHU de Rouen, INSERM EMI-9906, IFRMP Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France
  7. 7INSERM U434 CEPH, 75010 Paris, France
  8. 8First Department of Internal Medicine, Sapporo Medical University, S.1, W.16, Chuo-ku, Sapporo 060-8543, Japan
  9. 9Department of Clinical Genetics, Karolinski Hospital, PO Box 60500, S-104 01 Stockholm, Sweden
  1. Correspondence to:
 Dr Simó Schwartz Jr
 Molecular Oncology and Aging Unit, Centre d’Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain;


Background: According to the international criteria for hereditary non-polyposis colorectal cancer (HNPCC) diagnostics, cancer patients with a family history or early onset of colorectal tumours showing high microsatellite instability (MSI-H) should receive genetic counselling and be offered testing for germline mutations in DNA repair genes, mainly MLH1 and MSH2. Recently, an oncogenic V600E hotspot mutation within BRAF, a kinase encoding gene from the RAS/RAF/MAPK pathway, has been found to be associated with sporadic MSI-H colon cancer, but its association with HNPCC remains to be further clarified.

Methods: BRAF-V600E mutations were analysed by automatic sequencing in colorectal cancers from 206 sporadic cases with MSI-H and 111 HNPCC cases with known germline mutations in MLH1 and MSH2. In addition, 45 HNPCC cases showing abnormal immunostaining for MSH2 were also analysed.

Results: The BRAF-V600E hotspot mutation was found in 40% (82/206) of the sporadic MSI-H tumours analysed but in none of the 111 tested HNPCC tumours or in the 45 cases showing abnormal MSH2 immunostaining.

Conclusions: Detection of the V600E mutation in a colorectal MSI-H tumour argues against the presence of a germline mutation in either the MLH1 or MSH2 gene. Therefore, screening of these mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC.

  • HNPCC, hereditary non-polyposis colorectal cancer
  • IHC, immunohistochemistry
  • MMR, mismatch repair
  • MSI, microsatellite instability
  • BRAF
  • diagnostics
  • hereditary non-polyposis colorectal cancer
  • microsatellite instability
  • mismatch repair
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  • This work was supported by the Spanish Fondo de Investigaciones Sanitarias (grant number: FIS 01/1350), Spain; the Sigrid Juselius Foundation, European Commission (QLG2-CT-2001-01861); the Finnish Cancer Society, Academy of Finland (44870, Finnish Center of Excellence Program 2000–2005), and Finnish Cultural Foundation, Finland; Fundação para a Ciência e a Tecnologia, Portugal (projects: POCTI/35374/CBO/2000 and POCTI/CBO/40820/2001); the Dutch Cancer Foundation (grant number: 99-1962); and the Swedish Cancer Society.

  • Conflict of interest: none declared.

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