The risk for breast cancer and many other forms of cancer is increased with Li-Fraumeni syndrome (LFS), a genetic autosomal dominant cancer syndrome. A diagnosis of LFS is made when all of the following characteristics are present in a family:
Sarcoma at less than 45 years of age, and
A first-degree relative, such as parent, sibling, or child, with cancer at less than 45 years of age, and,
A first- or second-degree relative (aunt, uncle, or grandparent) with cancer at less than 45 years of age or sarcoma at any age
The majority of LFS (about 70%) is caused by mutations in a gene on chromosome 17 known as TP53, which encodes the protein p53. Another form of Li-Fraumeni syndrome is caused by mutations in the CHEK2 gene, and a third LFS locus has been mapped to chromosome 1q23. Mutations in TP53 confer an increased risk for early onset breast cancer, childhood sarcoma, osteosarcoma, brain tumors, leukemia, and adrenocortical carcinoma.
People with a TP53 mutation have a 50% chance of developing one of the associated cancers by age 40 and a 90% chance of developing cancer by age 60. Breast cancer appears to be the greatest risk for women, but less than 1% of all breast cancer is thought to be related to LFS. For those affected by LFS, breast cancers generally occur in premenopausal women.
The TP53 gene is a tumor suppressor gene, which usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. With LFS, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends on where (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. The process of tumor development actually requires mutations in multiple growth control genes. Loss 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 biological environmental exposures or chance errors in cell replication.
Some individuals who have inherited a germline TP53 mutation never develop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. 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, however, have a 50/50 chance to pass the mutation on to the next generation.
It is also important to remember that the TP53 gene is not located on the sex chromosomes. Therefore, mutations can be inherited from the mother's or the father's side of the family.