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What is Li–Fraumeni syndrome and explain in detail?
Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients. This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.
The syndrome is linked to germline mutations of the p53 tumor suppressor gene, which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited, or can arise from mutations early in embryogenesis, or in one of the parents germ cells.

Presentation
Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout ones life.

Pathology
LFS1: Mutations in TP53

Normal conditions: TP53 is a tumor suppressor gene on chromosome 17 that normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 typically become expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce apoptosis of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells.
Mutant conditions: Mutations of TP53 can inhibit its normal function, and allow cells with damaged DNA to continue to divide. 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.
Dominant negative mutations: Most individuals with Li–Fraumeni syndrome are heterozygous for a mutant TP53 gene, and some p53 mutants can inhibit the function of the wild-type p53 in a dominant negative manner. Mutated p53 proteins are typically more stable than wild-type, and can inhibit the activity of the wild-type protein in suppressing cell proliferation and in inducing cell cycle arrest. Due to the mutant p53 being able to inhibit some wild-type p53, damaged cells are at an even greater susceptibility to proliferate and become transformed, resulting in cancer.LFS2: mutations in CHEK2
Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene; it regulates the action of p53 and is activated by ATM, which detects DNA damage, and in this way, DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death).
LFS-L:
Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like". LFS-like individuals generally do not have any detectable p53 mutations, and tend to be diagnosed on either the Birch or Eeles criteria.
A third locus has been mapped to the long arm of chromosome 1 (1q23), but no gene has yet been identified.Another locus that has been linked to this syndrome is CDKN2A-CDKN2B.

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%)