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Suggested improvements for Li–Fraumeni Syndrome article from article page:

Characteristics: Cite sources

Epidemiology: Expand information and cite sources

Pathology: Add citations and reliable sources

Clinical: Cite sources

Diagnosis: Add citations of secondary and tertiary sources, may contain original research : (this is haley= I believe I found appropriate secondary source in order to validate original research; criteria was indeed mentioned in secondary source that Jake shared)

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Li–Fraumeni syndrome is a disorder that predisposes those who are affected to different cancers. It follows an autosomal dominant inheritance pattern and is quite rare. Cancers commonly associated with this syndrome include breast, brain, soft-tissue, and bone cancers, among others. Affected individuals can have multiple cancers at different sites at one time and/or over the course of their lifetimes. 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. It is also involved in activating apoptosis, or programmed cell death. The mutations can be inherited, or can arise from de novo mutations early in embryogenesis, or in one of the parent's germ cells.

Characteristics

Li–Fraumeni syndrome is characterized by early onset of cancer Li–Fraumeni syndrome is characterized by early onset of cancer , a wide variety of types of cancers, and by having a close relative who had been diagnosed with cancer before the age of 45.

Epidemiology

Li–Fraumeni syndrome (LFS) is relatively rare; a study showed that only 2.8% of 397 patients in the Li-Fraumeni syndrome registry met the typical criteria for the disease. As of 2011, cases had been reported in more than 500 families.[3] The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified several families in which siblings or cousins of sarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome.[4][5] Identification of TP53 as the gene affected by mutation was suggested by the same approach. Over half of the cancers in Li-Fraumeni families had been previously associated with inactivating mutations of the p53 gene,.

Clinical

Malignant cancers characteristic of Li-Fraumeni syndrome include sarcomas, brain tumors, adrenocortical carcinoma, and breast cancer; these make up about 70% of all LFS-related cancers and tend to occur earlier in LFS patients than the general population. Early onset breast cancer accounts for 25% of all the cancers in this syndrome, followed by soft tissue sarcomas (14.3%), adrenal gland tumors (13%), bone sarcoma (11%) and brain tumors - especially glioblastomas - (11%). Other tumours reported in this syndrome but not yet proved to be linked with it include melanoma, Wilm's and other kidney tumors, hepatacellular carcinoma, leukemia, lymphoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal and prostate cancers.

It has been suggested that up to 33% of sarcoma patients, 80% of children with adrenocortical carcinoma, and 2-10% of brain tumor patients are carriers of a p53 mutation. It is estimated that half of LFS patients will develop cancer by the time they are 40, and 90% will develop cancer by the age of 60, with female carriers having a higher risk than males . Roughly 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, as well as increased estrogen levels in females.

Diagnosis

If any of the following criteria are applicable to a proband, then Li- Fraumeni syndrome may be diagnosed:

• proband below the age of 45 has been diagnosed with a sarcoma,
• has a first- degree relative below that age of 45 diagnosed with cancer, and
• has any other first- degree or second- degree relatives below the age of 45 diagnosed with any type of cancer or diagnosed with a sarcoma at any age.

According to Birch and his colleagues, LFS may also be diagnosed if any of the following criteria are met:

• a proband under the age of 45 diagnosed with an adrenocortical tumor, or had been diagnosed in early childhood with a tumor, brain tumor, or sarcoma,
• has a first- degree or second- degree relative at any age with a typical LFS tumor or sarcoma, and
• has a first or second- degree relative that has been diagnosed with any cancer at the age of 60 and under.

The following criterion may also be met, as described by Eeles:

• an individual who is either a first or second- degree relative that presents with a clustering of two typical LFS tumors, at any age.

Management

Once a patient is tested and it is determined they have Li-Fraumeni Syndrome there are proactive clinical management tools they can use to reduce the risks of developing cancers at a later date. One facet of management is being proactive with screening for breast cancer. Female patients with Li-Fraumeni Syndrome should begin monthly self breast exams starting at age 18. In addition to these exams, clinical breast exams by a health care provider should be performed twice a year and mammogram or MRI breast screenings should be performed once a year starting at age 20-25 or 10 years before the earliest onset of cancer seen within other affected family members with Li-Fraumeni Syndrome. Another more aggressive form of management for breast cancer is a proactive mastectomy to remove the breast tissue before cancer has a chance to develop. This can be effective in stopping breast cancer but not very effective overall as breast cancer is not as likely as cancers of other major organs in patients with LFS.

The constant surveillance continues when looking at managing risks of cancers of other organs. Treatment recommendations include a complete physical and neurologically exam each year to check thoroughly for signs of developing cancer. Regular colonoscopies every 2 to 5 years are recommended to monitor possible developments of colorectal cancers. One treatment concern for LFS patients is the use of radiation therapy to treat developing cancers. It is highly recommended that LFS patients not use radiotherapy to treat developing cancers because the risks of secondary cancers emerging as a result of radiation could be higher in LFS patients than in the general population. A study of the cancer treatment of a patient with LFS found that treatment of her breast cancer with radiation lead to the development of a small-cell lung cancer and colon cancer, both within the field of the radiation during the treatment of her breast cancer. Studies of mice cells without TP53 found them to be overly sensitive to radiation and more likely to develop cancers.

Recommendations

For families and individuals carrying the mutation or already affected by LFS, the following are recommended:

• Regular skin and neurologic exams
• Cancer screenings including breast exams and mammograms, colonoscopies, and even MRIs
• Genetic counseling for affected individuals and their families
• Reducing exposure to potential carcinogens like smoking, sun exposure, and radiation

Genetic testing is an option for those who wish to undergo it. Testing positive for the TP53 mutation may mean informing other family members to get tested and starting preventative/screening measures like the ones above. Genetic counselors help individuals and families navigate these sometimes tricky and controversial situations.

CHK1 and CHK2 associated Li-Fraumeni Syndrome.

CHK1 and CHK2 are genes that are associated with cell cycle regulation that code for Checkpoint Kinase 1 and Checkpoint Kinase 2 respectively. They both function as protein kinases and have effects on the function of TP53, the protein primarily responsible for Li-Fraumeni Syndrome. The normal function of CHK1 is to phosphorylate Cdc25c in the presence of damaged DNA. This halts the cell cycle in the G2 phase, stopping mitosis. CHK2 functions to phosphorylate TP53 at DNA damage sites. Without these functions, there is a lack of control of the cell cycle, leading to uncontrolled cell growth and cancer phenotypes similar to Li-Fraumeni Syndrome.

Multiple studies have been performed to examine the contribution of CHK2 mutations to the development of Li-Fraumeni Syndrome phenotype. They have generally found that within LFS and LFS-like families, there was only one mutation of CHK2 observed. They also found that the presence of the CHK2 mutation did not correlate with expression of the Li-Fraumeni Syndrome phenotype, leading to their stated conclusions that CHK2 was not involved in LFS. Although CHK1 has been shown to play a role in cell cycle regulation and the regulation of TP53, mutations for it have not been identified in Li-Fraumeni Syndrome families.

Mutations in TP53

• Normal Conditions: TP53 is a tumor suppressor gene 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 become immortalized, and divide in an uncontrolled manner 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.[3] 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.[6] 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.[3] However, at a high physiological pH, p53 is unable to assemble into a tetramer.[3] 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.[7] 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.