Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz–Jeghers syndrome1,2 (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p (ref. 3). We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1 (ref. 4), has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1 (ref. 5), and weaker similarity to many other protein kinases. Peutz–Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.
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This study was aided by grants from the Helsinki University Central Hospital, the Academy of Finland, the Finnish Cancer Society, the Finnish Medical Society Duodecim, the Ida Montin Foundation, the Jalmari and Rauha Ahokas Foundation, the 350th Anniversary Foundation of the University of Helsinki, Leiras, the Emil Aaltonen Foundation, the UK Cancer Research Campaign, the ICRF, the Institute of Cancer Research, the U.S. Department of Energy, the Otago Medical School Bequest Funds, the Cancer Society of New Zealand and The Wellington Division of the Cancer Society of New Zealand. We thank K. Honkanen, M. Veini, T. Kosonen, S. Lindh, S. Lindroos, K. Collin, A. Georgescu, L.Gordon and R. Hamoudi for technical assistance; W. El-Rifai, K. Virtaneva, S. Ranta and S. Ezer for help with methodology; A. Moisio for control samples; D. Jenne for unpublished mapping data; the many PJS families for their collaboration; and the following clinicians for PJS samples: I. Ellis, S. Hodgson, T.Iwama, S. Loff, P. Zauber, C. Marchere, J. Sampson, S. Davies, I. Talbot, J. Wyke, R. Houlston, O. Suomalainen, F.M. Giardiello, S. R. Hamilton, S. B. Gruber, C. Eng, S. A. Lynch, A. Hunter and G. Mettler, and the polyposis registry, St Mark's Hospital.
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