Li–Fraumeni syndrome


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 syndrome.
The syndrome is linked to germline mutations of the p53 tumor suppressor gene, which encodes a transcription factor 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 parent's 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 one's life.

Pathology

LFS1: Mutations in TP53
LFS2: mutations in CHEK2
Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the CHEK2 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.
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, 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 is about 50% by age 30 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, bone sarcoma, and brain tumors - especially glioblastomas -. 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, hepatacellular 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. About 2-3% of osteosarcomas, 9% of rhabdomyosarcomas, and 7-20% of patients with multiple primary tumours have p53 mutations.
Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life.

Diagnosis

Li–Fraumeni syndrome is diagnosed if these three criteria are met:
Other criteria have also been proposed:
A third criterion has been proposed:
and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time.

Chompret criteria

A 2015 revision of the traditional Chompret criteria for screening has been proposed - a proband who has:
Recommendations for individuals from families affected by the syndrome include:
Li–Fraumeni syndrome is relatively rare; as of 2011, cases had been reported in more than 500 families. The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome. Identification of TP53s the gene affected by mutation was suggested by the same approach. Over half of the cancers in LFS families had been previously associated with inactivating mutations of the p53 gene and in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated TP53'' gene.