THE ROLE OF MMAC1 MUTATIONS IN EARLY-ONSET BREAST-CANCER - CAUSATIVE IN ASSOCIATION WITH COWDEN-SYNDROME AND EXCLUDED IN BRCA1-NEGATIVE CASES

Cowden syndrome (CS) is an autosomal dominant disorder associated with the development of hamartomas and benign tumors in a variety of tissu es, including the skin, thyroid, breast, endometrium, and brain. It ha s been suggested that women with CS are at increased risk for breast c ancer. A locus for CS was recently defined on chromosome 10 in 12 fami lies, resulting in the identification of the CS critical interval, bet ween the markers D10S215 and D10S541. More recently, affected individu als in four families with CS have been shown to have germ-line mutatio ns in a gene known as ''PTEN,'' or ''MMAC1,'' which is located in the CS critical interval on chromosome 10. In this study, we report three novel MMAC1 mutations in CS and demonstrate that MMAC1 mutations are a ssociated with CS and breast cancer. Furthermore, we also show that ce rtain families and individuals with CS do not have mutations in the co ding sequence of MMAC1. Finally, we did not detect MMAC1 mutations in a subpopulation of individuals with early-onset breast cancer, suggest ing that germ-line mutations in this gene do not appear to be common i n this group.