Li-Fraumeni Syndrome

This content has been reviewed and approved by

William J. Gradishar, MD FACP
Director, Breast Medical Oncology, Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine

The risk for breast cancer is increased with Li-Fraumeni syndrome (LFS). This is a rare inherited cancer syndrome. A diagnosis of LFS is made when all of the following characteristics are present in a family: 

• Sarcoma (a type of cancer) before 45 years of age
• A first-degree relative with cancer before 45 years of age
• A first- or second-degree relative with cancer before 45 years of age or sarcoma at any age

What causes LFS?

The majority of cases of LFS (about 70 percent) are caused by mutations in a gene on chromosome 17 known as p53. Mutations in this gene increase the risk of early onset breast cancer, childhood sarcoma, osteosarcoma (bone cancer), brain tumors, leukemia, and cancer in the adrenal glands. People with a p53 mutation have a 50 percent chance of developing one of the associated cancers by age 50. For women, the risk of breast cancer is 49 percent by age 44 and 60 percent over a lifetime.

The p53 gene is a tumor suppressor gene. It usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be altered (mutated) before a person gets cancer. With LFS, the first mutation is inherited from either the mother or the father. It is therefore present in all cells of the body. This is called a germline mutation.

Whether a person who has a germline mutation gets cancer and where the cancer occurs depend on where (in which cell type) the second mutation occurs. For example, if the second mutation is in the breast, then breast cancer may develop. If it is in the bone, then osteosarcoma may develop. But other mutations must occur as well for cancer to develop. Mutation of both copies of p53 is just the first step in the process. What causes these additional mutations is unknown. Possible causes include chemical, physical, or biologic agents in the environment or chance errors that happen when cells reproduce.

Some people who have inherited a germline p53 mutation never develop cancer because they never get the second mutation. This can make the cancer appear to skip generations in a family, when in reality the mutation is present. People with a mutation, regardless of whether they develop cancer, have a 50-50 chance of passing it on to their children.

The p53 gene is not located on the sex chromosomes. This means that mutations can be inherited from the mother's or the father's side of the family.