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The majority of LFS (about 70%) is caused by mutations in a gene on chromosome 17 known as p53. Mutations in p53 confer an increased risk for early onset breast cancer, childhood sarcoma, osteosarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Persons with a p53 mutation have a 50% chance of developing one of the associated cancers by age 50. For women, the risk of breast cancer specifically is 49% by age 44 with a lifetime risk of 60%.
The p53 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 upon 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 to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in cell replication.
Some individuals who have inherited a germline p53 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. Persons 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 p53 gene is not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father's side of the family.