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Screening SMAD1,SMAD2, SMAD3, andSMAD5 for germline mutations in juvenile polyposis syndrome
  1. S Bevana,
  2. K Woodford-Richensb,
  3. P Rozenc,
  4. C Engd,
  5. J Younge,
  6. M Dunlopf,
  7. K Nealeg,
  8. R Phillipsg,
  9. D Markieh,
  10. M Rodriguez-Bigasi,
  11. B Leggette,
  12. E Sheridanj,
  13. S Hodgsonk,
  14. T Iwamal,
  15. D Ecclesm,
  16. W Bodmern,
  17. R Houlstona,
  18. I Tomlinsonb
  1. aSection of Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Sutton, UK, bMolecular and Population Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK, cDepartment of Gastroenterology, Tel Aviv Medical Centre and Medical School, IL-64239 Tel Aviv, Israel, dTranslational Research Laboratory, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115-6084, USA, eConjoint Gastroenterology Laboratory, Clinical Research Centre, Royal Brisbane Hospital Foundation, Herston, Brisbane, Australia, fMRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK, gPolyposis Registry, St Mark’s Hospital, Harrow HA1 3UJ, UK, hMolecular Genetics Laboratory, Dunedin School of Medicine, Dunedin, New Zealand, iRoswell Park Cancer Institute, Buffalo, New York 14263, USA, jDepartment of Clinical Genetics, Royal Hospital for Children, St Michael’s Hill, Bristol, UK, kDepartment of Clinical Genetics, Guy’s Hospital, St Thomas’s Street, London SE1 9RT, UK, lCentre for Polyposis and Intestinal Diseases, Bunkyo-Ku, Tokyo, Japan, mWessex Regional Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK, nCancer Immunogenetics Laboratory, ICRF, Institute of Molecular Medicine, Oxford OX3 9DS, UK
  1. Dr R Houlston, Molecular and Population Genetics Laboratory, 4th Floor, Imperial Cancer Research Fund, London WC2A 3PX, UK.


BACKGROUND AND AIMS Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in theSMAD4 (DPC4) gene, providing further evidence for the importance of the TGFβ signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especiallySMAD2 (which, likeSMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when “knocked out” in mice),SMAD5, and SMAD1.

METHODS SMAD1,SMAD2, SMAD3, andSMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4mutations.

RESULTS No mutations were found in any of these genes. A G–A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls.

CONCLUSIONS It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas.SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.

  • juvenile polyposis
  • SMAD
  • Abbreviations used in this paper

    conformation specific gel electrophoresis
    juvenile polyposis syndrome
    transforming growth factor
  • Statistics from

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  • Abbreviations used in this paper

    conformation specific gel electrophoresis
    juvenile polyposis syndrome
    transforming growth factor
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