Nature Genetics
16, 64 - 67 (1997)
doi:10.1038/ng0597-64
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndromeDanny Liaw1, 2, *, Debbie J. Marsh4, *, Jing Li1, 2, Patricia L. M. Dahia4, Steven I. Wang1, 2, Zimu Zheng4, Shikha Bose1, Katherine M. Call6, Hui C. Tsou3, Monica Peacoke2, 3, Charis Eng4, 5, 7
& Ramon Parsons1, 2, 8
1Departments of Pathology, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, New York 10032, USA.
2Departments of Medicine, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, New York 10032, USA.
3Departments of Dematology, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, New York 10032, USA. .
4Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, D920C, Boston, Massachusetts 02115, USA.
5CRCHuman Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, UK.
6Genome Therapeutics Corporation, Waltham, Massachusetts, USA.
*D.L & D.J.M. contributed equally to this work.
7e-mail: charis_eng@macmailgw.dfci.harvard.edu.
8e-mail: repl5@columbia.edu. Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin1−2. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis3−4. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases5. A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer6. Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers7. Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families. We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
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