GERMLINE MUTATIONS OF THE PTEN GENE IN COWDEN-DISEASE, AN INHERITED BREAST AND THYROID-CANCER SYNDROME

Cowden disease (CD) is an autosomal dominant cancer predisposition syn drome associated with an elevated risk for tumours of the breast, thyr oid and skin(1-2). Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis(3-4). The common feature of t hese diseases is a predisposition to hamartomas, benign tumours contai ning differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within ch romosome 10q23 is likely to be responsible for both of these diseases( 5). A candidate tumour suppressor gene (PTEN) within this region is mu tated in sporadic brain, breast and prostate cancer(6). Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers(7) . Mutational analysis of PTEN in CD kindreds has identified germline m utations in four of five families, We found nonsense and missense muta tions that are predicted to disrupt the protein tyrosine/dual-specific ity 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 type s within an organ during development.