Genetics and Genomics

British Journal of Cancer (2003) 89, 308–313. doi:10.1038/sj.bjc.6601030 www.bjcancer.com
Published online 15 July 2003

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

W Lim1, N Hearle1, B Shah1, V Murday2, S V Hodgson3, A Lucassen4, D Eccles4, I Talbot5, K Neale6, A G Lim7, J O'Donohue8, A Donaldson9, R C Macdonald10, I D Young11, M H Robinson12, P W R Lee13, B J Stoodley14, I Tomlinson15, D Alderson16, A G Holbrook17, S Vyas18, E T Swarbrick19, A A M Lewis20, R K S Phillips6 and R S Houlston1

  1. 1Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
  2. 2Department of Genetics, St. Georges' Hospital, London SW17 0QT, UK
  3. 3Department of Clinical Genetics, Guy's Hospital, London SE1 9RT, UK
  4. 4Wessex Clinical Genetics Service, The Princess Anne Hospital, Southampton SO16 5YA, UK
  5. 5Academic Department of Pathology, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK
  6. 6Polyposis Registry, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK
  7. 7Department of Gastroenterology, Epsom General Hospital, Surrey, KT18 7EG, UK
  8. 8Department of Gastroenterology, University Hospital Lewisham, London SE13 6LH, UK
  9. 9Department of Clinical Genetics, St Michael's Hospital, Bristol BS2 8EG, UK
  10. 10Department of Surgery, Huddersfield Royal Infirmary, Huddersfield HD3 3EA, UK
  11. 11Department of Genetics, City Hospital, Nottingham NG5 1PB, UK
  12. 12Department of Surgery, City Hospital, Nottingham NG5 1PB, UK
  13. 13Department of Surgery, Hull Royal Infirmary, Hull HU3 2JZ, UK
  14. 14Department of Surgery, Eastbourne Hospital, East Sussex BN21 2UD, UK
  15. 15Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK
  16. 16Department of Surgery, Bristol Royal Infirmary, Bristol BS2 8HW, UK
  17. 17Department of Surgery, Royal United Hospital, Bath BA1 3NG, UK
  18. 18Department of Medicine, Salisbury District Hospital, Salisbury SP2 8BJ, UK
  19. 19Department of Gastroenterology, New Cross Hospital, Wolverhampton WV10 0QB, UK
  20. 20Department of Surgery, Royal Free Hospital, London NW3 2QG, UK

Correspondence: Dr W Lim, E-mail: wlim@icr.ac.uk

Received 21 August 2002; Revised 27 January 2003; Accepted 1 April 2003.

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Abstract

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz–Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27–73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype–phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Keywords:

Peutz–Jeghers syndrome, LKB1/STK11, mutation, cancer risk