ALLELIC IMBALANCE, INCLUDING DELETION OF PTEN MMACI, AT THE COWDEN DISEASE LOCUS ON 10Q22-23, IN HAMARTOMAS FROM PATIENTS WITH COWDEN SYNDROME AND GERMLINE PTEN MUTATION/

Cowden disease (CD) is a rare, autosomal dominant inherited cancer syn drome characterized by multiple benign and malignant lesions in a wide spectrum of tissues. While individuals with CD have an increased risk of breast and thyroid neoplasms, the primary features of CD are hamar tomas. The gene for CD has been mapped by linkage analysis to a 6 cM r egion on the long arm of chromosome 10 at 10q22-23. Loss of heterozygo sity (LOH) studies of sporadic follicular thyroid adenomas and carcino mas, both component tumors of CD, have suggested that the putative sus ceptibility gene for CD is a tumor suppressor gene. Somatic missense a nd nonsense mutations have recently been identified in breast, prostat e, and brain tumor cell lines in a gene encoding a dual specificity ph osphatase, PTEN/MMACI, mapped at 10q23.3. Furthermore, germline PTEN/M MACI mutations are associated with CD. In the present study, 20 hamart omas from 11 individuals belonging to ten unrelated families with CD h ave been examined for LOH of markers flanking and within PTEN/MMACI. E ight of these ten families have germline PTEN/MMACI mutations. LOH inv olving microsatellite markers within the CD interval, and including PT EN/MMACI, was identified in two fibroadenomas of the breast, a thyroid adenoma, and a pulmonary hamartoma belonging to 3 of 11 (27%) of thes e patients. The wild-type allele was lost in these hamartomas. Semi-qu antitative PCR performed on RNA from hamartomas from three different t issues from a CD patient suggested substantial reduction of PTEN/MMACI RNA levels in all of these tissues. The LOH identified in samples fro m individuals with CD and the suggestion of allelic loss and reduced t ranscription in hamartomas from a CD patient provide evidence that PTE N/MMACI functions as a tumor suppressor in CD. (C) 1998 Wiley-Liss, In c.