Clinical
The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome. The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukemia, lymphoma, and adrenocortical carcinoma. About 90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males and increased estrogen levels in females. The risks of sarcoma, female breast cancer, and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population. Other tumours reported in this syndrome, but not yet proved to be linked with it, include melanoma, Wilms and other kidney tumors, hepatocellular carcinoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal, and prostate cancers. Around 80% of children with adrenocortical carcinoma and 2–10% of childhood brain tumors have p53 mutations.
If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Further mutations in the DNA could lead to malignant cells that can travel to, and develop cancer in, different areas of the body. Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a TP53 mutation. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line TP53 mutations, the majority of which are missense mutations in the DNA-binding domain. These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal TP53 mechanism. Unique Brazilian mutation: Although other mutations leading to Li–Fraumeni syndrome have been found outside the DNA-binding domain, a mutation at codon 337 of the tetramerization domain of TP53 has shown a particularly high frequency. The tetramerization domain plays a major role in the oligomerization of the p53 protein, which exists as a tetramer. This mutation has only been found in Brazilian families, and is located in exon 10 of the TP53 gene. The mutation causes an amino acid change from arginine to histidine at codon 337. With pH in the low to normal physiological range (up to 7.5), the mutant protein forms normal oligomers and retains its suppressor function. However, at a high physiological pH, p53 is unable to assemble into a tetramer. This unique feature may contribute to why families with this particular mutation often show incomplete penetrance.