Li–Fraumeni Syndrome
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Li–Fraumeni syndrome (LFS) is a rare,
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
, 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 childhood
rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the neoplasm, tumor are identified as rhabdomyoblasts. The four ...
patients. The disease is also known as SBLA, for the Sarcoma, Breast, Leukemia, and Adrenal Gland cancers that it is known to cause.


Etiology

LFS is caused by
germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...
s (also called genetic variants) in the ''TP53''
tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
, which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The variants can be inherited, or can arise from mutations early in
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
, or in one of the parent's
germ cell A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they unde ...
s. LFS is thought to occur in about 1 in 5,000 individuals in the general population. In Brazil there is a common founder variant, p.Arg337, that occurs in about 1 in every 375 people.  LFS is inherited in an autosomal dominant fashion which means that a person with LFS has a 50% chance to pass the syndrome on in each pregnancy (and a 50% chance to ''not'' pass on the syndrome).


Clinical 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. LFS: Mutations in ''TP53'' ''TP53 ''is a
tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
on chromosome 17 that normally assists in the control of cell division and growth through action on the normal
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
. ''TP53'' typically becomes 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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells and the development of cancer. Pathogenic and likely pathogenic variants in the ''TP53'' gene 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). Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a ''TP53'' variant. 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. LFS-Like (LFS-L): Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-Like". LFS-L individuals generally do not have any detectable ''TP53'' variants, and tend to meet either the Birch or Eeles criteria.


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
glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...
s—(13%). Other tumours seen in this syndrome include
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
,
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
, and adrenocortical carcinoma. The table below depicts tumor site distribution of variants for families followed in the LFS Study at the National Cancer Institute's (NCI) Division of Cancer Epidemiology and Genetics (DCEG): About 95% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years lending females with this syndrome to have almost a 100% lifetime risk of developing cancer. Cancer Risks by Sex and Age Age          20 years old       40 years old      60 years old Men        25%                     40%                     88% Women  18%                     75%                     >95%


Diagnosis

Germline variants in the ''TP53'' tumor suppressor gene was discovered to be the primary cause of Li–Fraumeni syndrome in 1990. Li–Fraumeni syndrome is diagnosed if a person has a pathogenic or likely pathogenic ''TP53'' variant and/or if these three Classic Criteria are met: * The patient has been diagnosed with a sarcoma at a young age (below 45). * A first-degree relative has been diagnosed with any cancer at a young age (below 45). * Another first- or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age. LFS should also be suspected in individuals who meet other published criteria. 2015 Revised Chompret Criteria: * A proband with a tumor belonging to the LFS tumor spectrum (premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR * A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR * A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR * Breast cancer before age 31 years Birch Criteria for Li Fraumeni-like syndrome: * A proband with any childhood cancer, sarcoma, brain tumor, or adrenal cortical carcinoma diagnosed before age 45, AND * A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis, AND * A first- or second-degree relative with any cancer diagnosed before age 60 Eeles Criteria for Li Fraumeni-like Syndrome: * Two different tumors that are part of extended LFS in first- or second-degree relatives at any age (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical carcinoma, melanoma, prostate cancer, and pancreatic cancer). If an individual has a personal or family history concerning for LFS, they should discuss the risks, benefits, and limitations of genetic testing with their healthcare provider or a genetic counselor.


Management

Genetic counseling and
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
for the ''TP53'' gene can confirm a diagnosis of LFS. People with LFS require early and regular cancer screening following the "Toronto Protocol": * Children and adults undergo comprehensive annual physical examinations every 6 to 12 months * All patients consult a physician promptly for evaluation of lingering symptoms and illnesses * Ultrasound of abdomen and pelvis every 3 to 4 months from birth to age 18 years * Colonoscopy and upper endoscopy every 2 to 5 years beginning at age 25 or 5 years before the earliest known GI cancer in the family * Annual dermatological exam starting at age 18 years * Annual whole-body MRI * Annual brain MRI and neurological exam * Annual prostate-specific antigen (PA) starting at age 40 * Breast awareness beginning at age 18 * Clinical breast exam every 6 to 12 months starting at age 20 * Annual breast MRI age 20 to 29; annual breast MRI alternating with mammogram age 30 to 75 * Consideration of risk-reducing mastectomy (surgery to remove the breast tissue) * Families and individuals should consider participating in a peer-support group


References


Further reading

* * * {{DEFAULTSORT:Li-Fraumeni syndrome Cancer DNA replication and repair-deficiency disorders Hereditary cancers Rare diseases Single-nucleotide polymorphism associated disease Syndromes with tumors Transcription factor deficiencies Diseases named after discoverers