Lim, W.; Hearle, N.; Hodgson, S.V.; Phillips, R.K.S.; Houlston, R.S.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA91
Academic Journal
Introduction: Germline mutations in the LKB1 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS) a rare dominant disorder. In addition to hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with on increased risk of tumours at multiple sites. Follow up information on carriers is limited. Genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1 locus in 33 PJS families, and estimation of cancer risks in carriers and non-carriers. Methods: Thirty-three index patients with PJS were ascertained from within United Kingdom. Clinical information including details of any cancer in first- and second-degree relatives was collected on all patients. There was no selection of cases for a family history of cancer. Conformation sensitive gel electrophoresis was used for the initial screen of LKB1 mutations, followed by direct sequence analysis for mutational characterisation. Estimates of cancer risks were obtained from survival analyses and standardised mortality ratios using life table methods. Results: Germline mutations of LKB1 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1 mutations the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 was 47% (95% CI: 27 to 73%) with elevated risks of both gastrointestinal and breast cancer. Conclusion: PJS with germline mutations in LKB1 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of cancer risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1 negative cases as this group is likely to be heterogeneous.


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