INHERITED MUTATIONS IN PTEN THAT ARE ASSOCIATED WITH BREAST-CANCER, COWDEN-DISEASE, AND JUVENILE POLYPOSIS

PTEN, a protein tyrosine phosphatase with homology to tensin, is a tum or-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occu r in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dom inant multiple-hamartoma syndrome. PTEN was sequenced from constitutio nal DNA from 25 families. Germ-line PTEN mutations were detected in al l of live families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast a nd thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations we re not detected in 13 families at high risk of breast and/or ovarian c ancer. No PTEN-coding-sequence polymorphisms were detected in 70 indep endent chromosomes. Seven PTEN germ-line mutations occurred, five nons ense and two missense mutations, in six of nine PTEN exons. The wild-t ype PTEN allele was lost from renal, uterine, breast, and thyroid tumo rs from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue ad jacent to the breast and thyroid tumors. In RNA from normal tissues fr om three families, mutant transcripts appeared unstable. Germ-line PTE N mutations predispose to breast cancer in association with CD, althou gh the signs of CD may be subtle.