The Role of MMAC1 Mutations in Early-Onset Breast Cancer: Causative in
Association with Cowden Syndrome and Excluded in BRCA1-Negative Cases
Hui C. Tsou1, David H.-F. Teng3, Xiao Li Ping1,
Valeria Brancolini2, Thaylon Davis3, Rong Hu3,
Xiao Xun Xie1, Alexandra C. Gruener1, Carolina A.
Schrager1, Angela M. Christiano1, Charis Eng4,
Peter Steck5, Jurg Ott2, Sean V. Tavtigian3,
and Monica Peacocke1
1Department of Dermatology, Columbia University, College of Physicians and Surgeons, and
2Laboratory of Statistical
Genetics, Rockefeller University, New York;
3Myriad Genetics, Inc., Salt Lake City;
4Dana-Farber Cancer Institute,
Harvard Medical School, Boston; and
5Department of Neuro-Oncology and Pathology, The Brain Tumor Center,
University of Texas, M. D. Anderson Cancer Center, Houston
Abstract
Cowden syndrome (CS) is an autosomal dominant disorder associated with the
development of hamartomas and benign tumors in a variety of tissues, including the skin,
thyroid, breast, endometrium, and brain. It has been suggested that women with CS are at
increased risk for breast cancer. A locus for CS was recently defined on chromosome 10 in 12
families, resulting in the identification of the CS critical interval, between the markers
D10S215 and D10S541. More recently, affected individuals in four families with CS have
been shown to have germ-line mutations 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 associated with CS
and breast cancer. Furthermore, we also show that certain families and individuals with CS
do not have mutations in the coding sequence of MMAC1. Finally, we did not detect MMAC1
mutations in a subpopulation of individuals with early-onset breast cancer, suggesting that
germ-line mutations in this gene do not appear to be common in this group.
